CsA應(yīng)用難治性腎病綜合征

CsA在難治性腎病綜合征中的應(yīng)用難治性腎病綜合征的認(rèn)識(shí)Y排除:“假”難治Y“真”難治“真”難治-（1）Y

病理類型難治膜增生性腎小球腎炎（MPGN)局灶性節(jié)段性腎小球硬化癥(FSGS)膜性腎病(MN)中，重度系膜增生性腎小球腎炎（包括部分IgA腎病)腎小球輕微病變性腎?。ú糠郑℡病理類型輕，但出現(xiàn)：激素依賴激素抵抗激素加用其他免疫抑制藥物無(wú)效“真”難治-（2）難治性腎病綜合征的治療困惑Y

大劑量、長(zhǎng)療程糖皮質(zhì)激素的副作用Y

激素依賴、激素抵抗、頻繁復(fù)發(fā)

Y

細(xì)胞毒類的副作用及療效不佳Y

嘌呤抑制劑起效的相對(duì)緩慢難治性腎病綜合征復(fù)雜的免疫病理機(jī)制Y

循環(huán)及局部產(chǎn)生的免疫復(fù)合物在腎小球基底膜上沉積Y

炎癥細(xì)胞（單核、淋巴、中性粒細(xì)胞）浸潤(rùn)及損害Y

補(bǔ)體系統(tǒng)激活Y

各種細(xì)胞因子、趨化因子、粘附分子參與其中B7CD

28CD

40MHC

IIMAP

kinasesIL-2

ROtherT

cellB

cellTarget

of

rapmycinIL-15,

IL-7,

IL-9

et

al.Cyclin/CDKG2SGCCalcineurinFK506,

CsAGC(TOR)SirolimusT

cellGC-RIL-2NF-

BI

Banti-IL-2R舒萊、賽尼哌G1Aza

MCTXanti-CD40

anti-CD40Lde

novonucleoMtMiFde

syntheLsEiFsTCROCDK4T3CD40

L免疫細(xì)胞活化過(guò)程FTY720誘導(dǎo)歸巢免疫抑制劑第一代GC，CTX，AZA第二代CsAMMF，

FK506，

Sirolimus第三代第四代OKT3，Anti-IL2-R，

FTY720

，Anti-CD40，Anti-CD40L，Leflunomide，Anti-CD80/CD86，…化學(xué)結(jié)構(gòu)Y

新山地明活性成分－環(huán)孢素分子結(jié)構(gòu)=11個(gè)氨基酸構(gòu)成環(huán)狀多肽=分子結(jié)構(gòu)式:C62H111N11O12=分子量:1202.64CH3CHCHCH2H

CH

CH3CHON

CH

CMeValAbuMeGlyMeLeuMeLeuMeLeuCH3D-Ala

AlaMeLeuValO環(huán)孢素分子結(jié)構(gòu)作用機(jī)制Y

新山地明選擇性、可逆性抑制IL-2介導(dǎo)的T淋巴細(xì)胞增殖1)新山地明抑制輔助T淋巴細(xì)胞產(chǎn)生和釋放IL-22)新山地明抑制細(xì)胞毒性T淋巴細(xì)胞增殖3)新山地明抑制輔助T淋巴細(xì)胞/細(xì)胞毒性T淋巴細(xì)胞表面IL-2受體的表達(dá)，從而抑制兩種T淋巴細(xì)胞活性Cs

A抗原提呈細(xì)胞供體HLAIL-

1IL-2T輔助細(xì)胞CD

4T輔助細(xì)胞CD

8Cs

AIL-2受體IL-2受體IL-4,5,6受體IL-4

,5

,6CD

4CD

8B細(xì)胞B細(xì)胞CD

4CD

8B細(xì)胞補(bǔ)體激活腎免疫反應(yīng)的激活和擴(kuò)增臟細(xì)胞免疫

體液免疫T輔助細(xì)胞CD

4IL-

2Buurman

WA

et

al.

J

Immuol.

1986;136:4035-4039Morris

PJ.

Cyclosporine.

In:

Morris

PJ,

ed.

Kidney

transplantation:

Principles

and

Practice.

3rd

ed

1988:285-3174)新山地明作用于細(xì)胞周期的G0和G1期作用機(jī)制:新山地明不同于其他免疫抑制劑Y

與傳統(tǒng)免疫抑制劑相比,新山地明的選擇性作用機(jī)制=未導(dǎo)致骨髓抑制(動(dòng)物模型和人體研究證實(shí))1=顯著降低嚴(yán)重感染2-5=顯著降低排斥反應(yīng)發(fā)生率3-6Wish

JB.Transplant

Proc

1986;18(suppl

2):15-18CanadianMulticentre

TransplantStudy

Group.

NEngl

J

Med1986;314:1219-Canafax

DM

et

al.

Transplant

Proc

1986;18(suppl

1):192-6Shaffer

D

et

al.

Am

J

Surg

1987;153:381-6Sutherland

DER

et

al.

Am

J

Kidney

Dis

1985;5:318-27Feduska

NJ

et

al.

Transplant

Proc

1986;18(suppl

1):136-40藥代動(dòng)力學(xué)新山地明vs.傳統(tǒng)環(huán)孢素Y吸收

Y分布Y代謝/排泄群體間的用藥不穩(wěn)定Y

個(gè)體間吸收差異很大=個(gè)體間AUC曲線變化非常大=部分存在2個(gè)峰值Y

群體間血藥濃度/用藥不穩(wěn)定血濃度(在穩(wěn)定的移植患者中傳統(tǒng)環(huán)孢素的典型藥代動(dòng)力學(xué)圖象吸收:傳統(tǒng)環(huán)孢素局限性0

2

4

68

10

12時(shí)間（小時(shí)）30006009001200Y

個(gè)體內(nèi)吸收差異很大Y

導(dǎo)致群體內(nèi)血藥濃度/用藥不穩(wěn)定g/L)300012小時(shí)AUC（藥物暴露）(h.20001000029名穩(wěn)定腎移植患者,二次測(cè)定相隔1周,劑量不變?cè)S多患者藥物吸收后的血中藥物濃度差異顯著,可達(dá)3倍50004000吸收:傳統(tǒng)環(huán)孢素局限性Y

傳統(tǒng)環(huán)孢素的吸收局限性=吸收受多種因素影響=生物利用度變異大吸收:傳統(tǒng)環(huán)孢素局限性增加患者管理難度影響臨床療效傳統(tǒng)環(huán)孢素生物利用度%比例%吸收:傳統(tǒng)環(huán)孢素局限性源自劑型化學(xué)特性親脂性,不溶于水與水和GI分泌液接觸時(shí)形成大顆粒巨乳液高分子量GI粘膜通透性↓易被蛋白酶降解和滅活口服的吸收度低、變異大、不可預(yù)測(cè)降解和吸收需要膽鹽和胰酶參與吸收/血藥濃度受膽汁分泌和胃腸道動(dòng)力的影響Y

傳統(tǒng)環(huán)孢素的化學(xué)性質(zhì)導(dǎo)致其藥代動(dòng)力學(xué)局限性新山地明:全新劑型優(yōu)化化學(xué)特性Y

新山地明劑型的進(jìn)步表面活性劑親水性溶劑親脂性溶劑環(huán)孢素原藥微乳化技術(shù)帶來(lái)新山地明?的問(wèn)世新山地明?是環(huán)孢素微乳濃縮劑型新山地明?是四種成分的精確平衡親脂性溶劑親水性溶劑表面活性劑環(huán)孢素新山地明:全新劑型優(yōu)化化學(xué)特性Y

新山地明與液體接觸后自然形成透明的微乳液環(huán)孢素原藥傳統(tǒng)環(huán)孢素劑型藥物與水相溶新山地明新山地明:全新劑型優(yōu)化化學(xué)特性Y

滿足環(huán)孢素最佳劑型的兩個(gè)標(biāo)準(zhǔn)最佳環(huán)孢素劑型標(biāo)準(zhǔn)

新山地明快速釋放環(huán)孢素全部腸道都可吸收藥物在被液體稀釋過(guò)程中，始終使環(huán)孢素在吸收窗內(nèi)保持微乳狀態(tài)山地明吸收：口服吸收百分比變異性較大，約為4%-26%。生物利用度：大多數(shù)病人隨著治療期的延長(zhǎng)，生物利用度逐漸提高，可從10.4%到治療后兩周的56.8%。在穩(wěn)定病人中，山地明口服液的絕對(duì)生物利用度范圍為20%-50%，平均34%。達(dá)峰時(shí)間：達(dá)峰時(shí)間為2到4小時(shí)，平均2.8小時(shí)。02507501000-

1峰濃度(Cmax)0

1

2

3

4

5

6

7

8

9 10

11

12

13Tmax用藥谷濃度(Cmin)AUC(Total

Exposure)時(shí)間(h)血藥濃度5

0(0ng/ml)用藥新山地明:全新劑型改善吸收=平均峰濃度=生物利用度(AUC)=達(dá)峰時(shí)間Y

傳統(tǒng)環(huán)孢素基礎(chǔ)藥代動(dòng)力學(xué)

Y

新山地明59%29%1小時(shí)新山地明:全新劑型改善吸收Y

新山地明吸收不受膽汁影響，優(yōu)于傳統(tǒng)環(huán)孢素0200400Cmax－Coh(ng/ml)600800新山地明傳統(tǒng)環(huán)孢素新山地明傳統(tǒng)環(huán)孢素T管開(kāi)放T管關(guān)閉N=

11N=

7N=

11N=

5新山地明:全新劑型改善吸收Y

新山地明的劑量與生物利用度呈線性關(guān)系，優(yōu)于傳統(tǒng)環(huán)孢素48例健康志愿者服用單劑傳統(tǒng)環(huán)孢素和新山地明后的劑量－AUC關(guān)系劑量(mg)05

,00010

,00015

,0000200400600800新山地明山地明－－AUC(ng/ml)－－藥代動(dòng)力學(xué):分布Y

環(huán)孢素廣泛分布于機(jī)體各組織中=濃度最高部位：肝臟、脂肪=其次：脾臟、腎臟、胰腺=在血液中41-58%：紅細(xì)胞4-9%：淋巴細(xì)胞5-12%：粒細(xì)胞33-47%：血漿藥代動(dòng)力學(xué):代謝與排泄Y

新山地明代謝=99%的在人體肝臟內(nèi)通過(guò)細(xì)胞色素P-450酶被代謝為約15種產(chǎn)物Y

新山地明排泄=代謝產(chǎn)物主要通過(guò)膽汁分泌=經(jīng)腸道排出體外=少部分（~6%）通過(guò)尿液排出體外=少于1%經(jīng)尿以原形排出新山地明藥代動(dòng)力學(xué)小結(jié)新山地明更易于患者管理Y

吸收更快速、更完全=生物利用度高，用藥量減少Y

劑量與生物利用度呈線性=易與調(diào)整劑量Y

血藥濃度變異性小/藥代動(dòng)力學(xué)穩(wěn)定=更便于監(jiān)測(cè)，更可預(yù)測(cè)藥物相互作用Y

增加環(huán)孢素血藥濃度的藥物鈣通道阻滯劑Diltizaem尼卡地平維拉帕米糖皮質(zhì)激素甲基強(qiáng)的松龍抗真菌藥物氟康唑

伊曲康唑酮康唑抗生素克拉霉素紅霉素其他藥物別嘌醇鈉溴隱亭氯奎丹那唑甲氨蝶呤對(duì)T淋巴細(xì)胞亞群有特異性抑制作用1,2,3輔助性T細(xì)胞（Th）和細(xì)胞毒性T細(xì)胞（Tc）為其主要靶細(xì)胞，作用于淋巴細(xì)胞激活的早期階段抑制T淋巴細(xì)胞合成和釋放白介素-2（IL-2）抑制IL-2受體（

IL-2R）的合成非免疫抑制作用4,5,6恢復(fù)基底膜的電荷屏障恢復(fù)基底膜的機(jī)械屏障新山地明?

治療腎病綜合征的最新作用機(jī)制Meyrier

A.

J

Nephrol

1997

:

10

(

1

):

14

-

24Sherach

EM.

Annu

Rev

Immunol.

1985

;

3

:

397

-

423

.Tejani

A,

Ingulli

E.

Contrib

Nephrol.

1995

;

114

:

1

-

5

.Ambatavanan

S,

Fauvel

JP

,

Sibley

RK,

Myers

BD,

J

Am

Soc

Nephrol

1996

;

7

:

290

-

8Zietse

R,

Wenting

GJ,

Kramer

P,

Schalekamp

MA,

Weimar

W.

Clin

Sci

(

Lond).

1992

Jun;

850Zietse

R,

Derkx

FH,

Schalekamp

MA,

Weimar

W.

Contrib

Nephrol.

1995

;

114

:

6

-

18

.鈣調(diào)免疫抑制劑—可能成為難治性腎病綜合征的理想藥物他克莫司：僅有小樣本及該例報(bào)道環(huán)孢素A：已有大量循證醫(yī)學(xué)證據(jù)CsA在難治性腎病綜合征中的應(yīng)用已有大量循證醫(yī)學(xué)證據(jù)Cyclosporin

versus

cyclophosphamide

forpatients

with

steroid-dependent

and

frequentlyrelapsing

idiopathic

nephrotic

syndrome:a

multicentre

randomized

controlled

trialPonticell

C,

et

al,Nephrol

Dial

Transplant.

1993;8(12):1326-32A

randomized

trial

of

cyclosporine

in

steroid-resistant

idiopathic

nephrotic

syndromePonticell

C,

et

al,Kidney

Int.

1993

Jun;43(6):1377-84Y

Treatment

of

idiopathic

nephrotic

syndrome

withcyclosporin

A

in

childrenHamed

RM,et

al

J

Nephrol.

1997

Sep-Oct;10(5):266-70Y

Cyclosporin

A

plus

prednisone

treatment

of

steroid-sensitive

frequently

relapsing

nephrotic

syndromechildrenAksu

N,etal,Turk

J

Pediatr.

1999

Apr-Jun;41(2):225-30Y

Long-term

results

of

cyclosporine-induced

remissirelapsing

nephrotic

syndrome

in

childrenKim

PK,et

al,Yonsei

Med

J.

1997

Oct;38(5):307-18Y

Cyclosporine

in

patients

with

steroid-resistantnephrotic

syndrome:

an

open-label,

nonrandomized,retrospective

study.Ghiggeri

GM,

et

al,

Clin

Ther.

2004

Sep;26(9):1411-8Y

Recurrence

of

severe

steroid

dependency

incyclosporin

A-treatedchildhood

idiopathicnephrotic

syndromeKemper

MJ,

et

al,

NDT.

2004

May;19(5):1136-41Y

C1-C2

point

monitoring

of

low-dose

cyclosporingiven

as

a

single

daily

dose

in

children

withsteroid-dependent

relapsing

nephroticsyndroY

Single-centre

experience

with

cyclosporin

in

1children

with

idiopathic

focal

segmentalglomerulosclerosisNakahata

T,

et

al,

Clin

Nephrol.

2005

Oct;64(4):258-63Mahmoud

I,

et

al,

Nephrol

Dial

Transplant.

2005

Apr;20(4):735-42YInitial

treatment

of

idiopathic

nephrotsyndrome

in

children:

prednisone

versuprednisone

plus

cyclosporine

A:a

prospective,

randomized

trialHoyer

PF,et

al,

J

Am

Soc

Nephrol.

2006

Apr;17(4):1151-7CsA在難治性腎病綜合征中需要關(guān)注的問(wèn)題Y療效：不同病理類型Y副作用：尤其是腎毒性Y復(fù)發(fā)問(wèn)題：腎病綜合征對(duì)CsA的反應(yīng)（回顧性分析）根據(jù)病理類型分析根據(jù)以前對(duì)激素敏感性分析INS(n=150)MCD(n=42)FSGS(n=68)敏感(n=66)抵抗(n=81)CR60(74%)14(21%)48(72%)24(30%)PR11(13%)19(28%)9(14%)21(26%)Failure11(13%)35(51%）9(14%)36(44%)Meyrier.

Karger,

basel:1995:28治療成人FSGS新山地明?

組激素抵抗型FSGS的患者緩解率69％，安慰劑組為4％安慰劑＋激素（n＝23）p＜0.001604020080新山地明?

組安慰劑組Cattran

DC

et

al.

Kid

Int

1999；56：2220－2226.新山地明?

＋激素（n＝26）緩解率：新山地明?

VS安慰劑）100治療成人FSGS長(zhǎng)期隨訪結(jié)果新山地明?

組部分緩解安慰劑組部分緩解新山地明?

組完全緩解122478104P

＜0.001P＜0.0560蛋白尿的緩解率（％）52隨訪時(shí)間(周)2004080100新山地明?

+低劑量激素治療26周之后，超過(guò)40%的激素抵抗型FSGS患者獲得持續(xù)緩解Cattran

DC

et

al.

Kid

Int

1999

;

56

:

2220

-26治療成人FSGS長(zhǎng)期隨訪結(jié)果新山地明?組安慰劑組兩組同一隨訪時(shí)間相比均為P<0.050204060

80100

120

140

160

180

200隨訪時(shí)間（周）22005040肌酐清除率(Ccr)下降3050%的患者比例201060隨訪4年時(shí)，新山地明?

組腎功能好于安慰劑組(P<0.05)Cattran

DC

et

al.Kid

Int

1999;56:2220-26治療成人MCD緩解情況對(duì)環(huán)孢素?zé)o反應(yīng)對(duì)環(huán)孢素有反應(yīng)Matsumoto

H

et

al.

Clinical

Nephrology

2001；55：143－148.單獨(dú)使用低劑量環(huán)孢素可以使成人MCD患者緩解312862024獲得緩解的患者6

數(shù)量81012全部病例n=11復(fù)發(fā)病例n=7首發(fā)病例n=4Mild

proteinuria<

4

g/d

+normal

renal

functionModerate

proteinuria>=4

to

<

8

g/d

+normal

renal

functionHeavy

proteinuria>

8

g/d

with

or

withoutrenal

insufficiencyACEI ARB,

dietaryprotein

restriction,Maintain

BP

<

125/75,Observe

for

6

moACEI ARB,

dietaryprotein

restriction,Maintain

BP

<

125/75,Observe

for

<=

6

moPersistentnephroticrangeproteinuriaPersistent

heavy

protein-uria

and/or

decreasingrenal

functionCytotoxic/steroidsCyclosporineCyclosporineCytotoxic/steroidsJ

Am

Soc

Nephrol,

16:

1188-1194,

2005治療成人MN治療成人MNYCyclosporin

A

treatment

for

idiopathicmembranous

nephropathyY

CSA

therapy

at

a

dosage

of

5

mg.kg-1.d-1

is

effectiveinducing

remission

of

nephrotic

syndrome

in

adultIMN

patients

within

three

monthsY

with

a

response

rate

of

80%Y

A

relatively

high

rate

of

relapse

(50%)

was

observedwithin

2

years

after

the

withdrawal

of

CsA

treatmentYao

X,

et

al,Chin

Med

J

(Engl).

2001

Dec;114(12):1305-8治療成人MNY

The

remission

of

nephrotic

syndromewith

cyclosporin

treatment

does

notattenuate

the

progression

ofidiopathic

membranous

nephropathyIMN

nephrotic

patients

treated

withprednisolone

and

low

doses

of

cyclosporin

Ashowed

a

high

remission

rate

of

nephroticsyndrome.Goumenos

DS,

et

al,

Clin

Nephrol.

2004

Jan;61(1):17-24治療IgANYLong

term

treatment

of

IgA

nephropathywith

cyclosporine

AY

CsA

significantly

lowered

moderate

to

high

proteinuria

in

patients

with

IgAN.Y

The

therapy

was

well

tolerated

and

side-

effects

were

not

so

severe

as

to

require

CsA

withdrawalRen

Fail.

2000

Jan;22(1):55-62兒童患者的療效Single-centre

experience

with

cyclosporin

106

children

with

idiopathic

focalsegmental

glomerulosclerosisCsA

is

effective

in

the

treatment

ofchildren

with

idiopathic

FSGS:a

high

relapse

rate

on

drug

withdrawalMahmoud

I,etal,Nephrol

Dial

Transplant.

2005

Apr;20(4):735-42兒童患者的療效環(huán)孢素治療兒童激素依賴型腎病綜合征環(huán)孢素是兒童激素依賴型腎病綜合征的有效治療藥物，86%的患兒對(duì)治療有反應(yīng)43

％43

％14

％43％完全反應(yīng)（在治療3個(gè)月后不再使用類固醇）43％部分反應(yīng)14％無(wú)反應(yīng)Garcia

C

et

al.

Transplant

Proc

1998；30：4156－57.兒童患者的療效環(huán)孢素治療兒童難治性腎病綜合征使用環(huán)孢素之前使用環(huán)孢素之后環(huán)孢素顯著降低腎病患兒尿蛋白Singh

A

et

al.

Pediatr

Nephrol

1999;13:26-32P=0.012103478全部FSGSMCDMPGN狼瘡腎炎HIV腎病尿蛋白g/24hP<0.00016P<0.0015P=0.03P<0.0001P=0.007P=0.06IgM腎病病理分型減少腎毒性YInitial

remission-inducing

effect

of

velow-dose

cyclosporin

monotherapy

forminimal-change

nephrotic

syndrome

inJapanese

adultsMatsumoto

H,

etal,

Clin

Nephrol.

2001

Feb;55(2):143-8減少腎毒性YC1-C2

point

monitoring

of

low-dosecyclosporin

a

given

as

a

single

daily

doin

children

with

steroid-dependentrelapsing

nephrotic

syndrome.Nakahata

T,et

al,Clin

Nephrol.

2005

Oct;64(4):258-63減少腎毒性YLong-term

treatment

of

focal

segmentalglomerulosclerosis

in

children

withcyclosporine

givenas

a

single

daily

dosChishti

AS,

etal,

Am

J

Kidney

Dis.

2001

Oct;38(4):754-60減少腎毒性YSingle-dose

daily

administration

ofcyclosporin

A

for

relapsing

nephroticsyndrome2.4+/-1.1

mg/kg

per

dayY

No

evidence

of

CsA

nephrotoxicitywas

ob