Mesto drugih savremenihMesto drugih savremenih ... · PDF fileMesto drugih savremenihMesto...

Mesto drugih savremenihMesto drugih savremenih imunosupresiva u lecenju p j

nefrotskog sindroma

Sanja Simic OgrizovicNefroloska klinika, KCSNefroloska klinika, KCS

Medicinski fakultet, Beograd

“TH spasavanja” u lecenjuTH spasavanja u lecenju nefrotskog sindroma

KOJI DRUGI - savremeni ??• Tacrolimus • mTOR-inhibitori

M kl k tit l• Monoklonska antitela

KOJI DRUGI - savremeni ??

• Tacrolimus • mTOR-inhibitori• Monoklonska antitela

Mehanizam dejstva tacrolimus-a Inhibise celijski cisklus izmedju G0 i G1, pretezno suprimira produkciju CK u Th-1 cel-inhibise celijski imuni odgovor

<

CN aktivira T ly (Th1) Trasnkripcija gena za CK

M k lid i IS i ljiMakrolidni IS iz gljive Streptomyces tsukubaensis 822kDa

Imunoloski efekti KNI

Tip celija EfektiTip celija Efekti

T limfociti expresiju IL2, IL3, IL4, TNF αlif ij k j l di l d k ij IL2proliferaciju koja sledi posle produkcije IL2

Ca2+ zavisnu exocitozu granula povezanih sa serin esterazom Inhibisu Ag –stimulisanu apoptozu

B limfociti Inhibisu prolifer. CK od strane vec produkcije T lyInhibisu proliferaciju koja sledi posle ligacije povrsine IGIndukuju apoptozu koja sledi posle aktivacije B ly

G l iti C 2+ i il l ih iGranulociti Ca2+ zavisnu exocilosu granula povezanih sa serin esterazom

Ponticelli C et Glassok R. Treatment of primary glomerulonephritis; Second edition, Oxford university press 2008.

Vodic za koriscenje Tac u GN IVodic za koriscenje Tac u GN I

1 Kontraindikovana primena kada : Cl cr <60 ml/min teska1. Kontraindikovana primena kada : Cl cr <60 ml/min, teska nekontrolisana HTA, odmakle TIN lezije u materijalu za bi ijbiopsiju.

2. Obazrivo kada: Cl cr 60-90 ml/min, i/ili srednje izrazene TIN

3. U bolesnika sa HTA zapoceti th samo kada je TA normalizovan uz th.

4. Inicjalna doza za Tac 0.1-0.2mg/kg/dnevno

5 Ako ni posle 6 meseci nema odgovora –lek je bez efekta5. Ako ni posle 6 meseci nema odgovora –lek je bez efekta (MGN duze se cak na odgovor)

Ponticelli C et Glassok R. Treatment of primary glomerulonephritis; Second edition, Oxford university press 2008.

Vodic za koriscenje Tac u GN IVodic za koriscenje Tac u GN I

6. U slucaju dobrog odgovora dozu postepeno smanjivati do do minamalne efektivne doze.

7. Redovna kontrola BF. Ukoliko sCr > 30% dozu Tac smanjiti do vracanja Cr na bazalni nivoj j

8. Stop Tac ukoliko sCR > 50% od bazalne vrednosti.

9 Sporadicna kontrola nivoa Tac u krvi9. Sporadicna kontrola nivoa Tac u krvi –

odrzavanje TAc <6 ng/ml.

10. Obratiti paznju na lekove koji interferiraju za TAc farmakokinetikom ili koji mogu da povecaju Ntox,

Ponticelli C et Glassok R. Treatment of primary glomerulonephritis; Second edition, Oxford university press 2008.

Kljucne reci: Tac and glomerulonephritis =56 radova

71990-2000 god.-eksperimentalni radovi

56

ci

34

refe

renc

123

Bro

j r

01

2007 2008 2009 2010 20112007 2008 2009 2010 2011

LN GN I

Combined therapy of Tac and steroid in CsA -resistant or dependent idiopathic FSGS a preliminar ncontrolled-dependent idiopathic FSGS a preliminary uncontrolled

study with prospective follow-up (25pts)

Compl.i

Partial remiss

Remissiont 3 /24h

Total remiss. remiss. part. < 3g/24h

Cs depend 5 (100%) 5 (100%)(5 pts) (100%)

Sec resist. 3 (42.8%) 2 (28.5%) 2 (28.8%) 7(100%)(7 pts) (100%)

Prim resist. 2 (15.3%) 3 (23%) 5

(13 pts) (38.4%)

Stable remission of prt in previous 28% CsA resistance and 48% CsA relapses

Segarra A. Nephrol Dial Transplant 2002; 17: 655-662

p p pAfter 6-12 month discounting. 13/17 (76%) relapsed

Treatment of FSGS in adults with tacrolimus monotherapy ( C )(6 pts + 5 pts prevous CsA)

Tac has a more potent immunosuppressive effect andmay be less toxic at therapeutic doses than CsA ??

Established remission but had

may be less toxic at therapeutic doses than CsA ??

P>0 05Established remission but haddeclining renal function

P>0.05

An improvement in renal function and a further reductionin proteinuria, although neither reached statisticalsignificance.

Change in 24-hour urinary protein excretion with Tactreatment of patients with NS and FSGS

(diamonds, mean values).Change in renal function in FSGS patients convertedfrom CsA and corticosteroids to Tac treatment.

Duncan N. et al Nephrol Dial Transplant (2004) 19: 3062–3067

(diamonds, mean values).

Tacrolimus monotherapy in membranous nephropathy:Tacrolimus monotherapy in membranous nephropathy:A randomized controlled trial Tacrolimus in MGN

(Tac 25 pts, Contr 23 pts)T 0 05 /k /d

Tac

Tac 0.05mg/kg/day

Controls

Probability of partial or complete remission

Percentage of complete (gray) and partial (white) remissions in the T and C group

M Praga et al. Kidney International 71, 924-930 (May (1) 2007)

Tacrolimus for the treatment of SLE with pure class V nephritis p p(18 patients + 19 historical controls)

Tac 0 1-0 2mg/kgTT/AzaTac 0.1 0.2mg/kgTT/AzaControls: Cyc/Aza Tac Aza

Serial trend of proteinuria during the study period. Serial trend of SLEDAI during the study period.

Tac group: complete 27.8 % and partial 50.0%, remission rates at 12 weeks. Control group: complete 15 8 and partial 47 4% remission rates at 12 weeks

Szeto C .C et al. Rheumatology 2008;47:1678–1681

Control group: complete 15.8 and partial 47.4%, remission rates at 12 weeks.

Tacrolimus rescue therapy in resistant oruncontrolled observational study

Tacrolimus rescue therapy in resistant orrelapsing cases of primary glomerulonephritis (No 15)

Prevous IS regiment: ster/cyc/MMF/CsA Tac 0.05mg/kgTT

Mean levels of proteinuria in patients with resistant or Individual changes in proteinuria during tacrolimust t t i ti t ith i t t l i i GN

p prelapsing primary glomerulonephritis treated with tacrolimus treatment in patients with resistant or relapsing primary GN

10/15 patients (60%) reached complete remission6/10 l d ft 4 8 ± 2 2 th f t li ithd l

Arikan H et al. J Nephrol 2008; 21: 713-721

6/10 relapsed after a mean 4.8 ± 2.2 months from tacrolimus withdrawal

1. Toksicni efekti Tac/Cs Toksicni efekti Tacrolimus Ciklosporin Nefrotoksicnost slicno slicnoNefrotoksicnost slicno slicno

Hipertenzija manje vise

Di b t ll i (di kt t jDiabetes mell vise (direktno na ostrvca pankreasa)

manje

Deramtoloski redje, samo alopecija izrazeni

GIT ucestale stolice cesce redje

Neuroloski cesce (gubitak sluha) redje Neuroloski (g ) j

Hiperholesterol. redje cesce

Poremecaj elektrol 1/3 bol ima hiperK hipoMg cesto hiperK hipoMg cestoPoremecaj elektrol 1/3 bol. ima hiperK, hipoMg cesto hiperK, hipoMg cesto

Malignitet slicno (PTLT kod dece cesce) slicno

T d li liTrudnoca slicno slicno

Ponticelli C et Glassok R. Treatment of primary glomerulonephritis; Second edition, Oxford university press 2008.

2. Resistentni ili relapsirajuci GN kod odraslih

3. Kod dece (Ch dh S t l Effi d f t f t li l i i(Choudhry S et al. Efficacy and safety of tacrolimus versus cyclosporine in children with steroid-resistant nephrotic syndrome: a randomized controlled trial. m J Kidney Dis. 2009; 53(5):760-9 (N of pts 41)

KOJI DRUGI - savremeni ??

• Tacrolimus• mTOR-inhibitori• Monoklonska antitela

mTOR inhibitori

• Sirolimus (rapamycin) (polu-zivot 62h)( p y ) ( )• Everolimus (derivat sirolimusa) (bolja

bioraspolozivost polu zivot 26h)bioraspolozivost- polu-zivot 26h)

Makrolidni lakton iz gljive Streptomyces hygroscopicus

Mehanizam dejstva sirololimus-aInhibise celijski ciklus izmedju G1 i S+protektivni efekat na endotelijum+antiTU aktivnost

VEGFonkogeni prtg p

CMV

PI3-k pkB

PI3-k = phosphtidylinositol-3-kinaza pkB=protein-kinaza B

23Kljucned reci: Sir and glomerulonephritis =23 rada

Od 2000-2011. god

+-

experiment klinicki

A Prospective, Open-Label Trial of Sirolimus in theTreatment of FSGS (N 21 pts)

17/21 t t/24h 12/21 t l t i l t i i

Tumlin J et al. Clin J Am Soc Nephrol 1: 109–116, 2006

17/21 pts prt/24h; 12/21 pts complete or incomplete remission

Toksicni efekti mTOR inhibitoraToksicni efekti mTOR inhibitora 1. Hiperlipidemija 2. Toksican efekat na k. srz ( Tr i Er ) 3. Nefrotoksicnost (proteinurija u 1/3 bolesnika) (p j )4. Zarastanje rana (antiproliferativno dejstvo) 5 Intersticijalna pneumonija5. Intersticijalna pneumonija 6. Ulceracije sluzokoze usta-zavisno od doze leka 7. Bolovi u zglobovima-zavisno od doze leka 8. Edemi -zavisno od doze leka 9. Trudnoca-nedovoljno informacija 10. Malignitet-anti neoplasticne osobine10. Malignitet anti neoplasticne osobine

Ponticelli C et Glassok R. Treatment of primary glomerulonephritis; Second edition, Oxford university press 2008.

Terapeutska uloga sirolimusa u bubreznim bolestima koje nisu vezane za Tx

• Paradoksalno pogorsanje bubrezne disfunkcije kada je GFR < 40 ml/min/1.73 m2 uz prt > 300 mg/d).

• Uzrok moze biti delom, zbog inhibicije kompenzatorne reparacije glomerulskih kapilara kroz supresiju proliferacije endotelnih celija I angiogenog faktora rasta kojeg produkuju podociti.

Rangan GK. Pharmacol Ther. 2009; 123(2):187-206

KOJI DRUGI - savremeni ??

• Tacrolimus• mTOR-inhibitori• Monoklonska antitela

Monoklonska antitelaMonoklonska antitela

• Rituximab (Anti CD20 At) • Almtuzumab (anti CD52 At)Almtuzumab (anti CD52 At)• Eculizumab (anti complment C5)• Anti TNF (etanercept, infliximab,

adalimumab) ada u ab)

Ponticelli C et Glassok R. Treatment of primary glomerulonephritis; Second edition, Oxford university press 2008.

Mehanizam dejstva rituximab-a Braza eliminacija B ly

Glavne karakterstike rituximabaGlavne karakterstike rituximaba• Himericno monoklonsko At sa velikim afinitetom zaHimericno monoklonsko At sa velikim afinitetom za

CD20 Ag exprimiranom na B ly. • Moguce dejstvo u autoimunim bolestima: smanjuje• Moguce dejstvo u autoimunim bolestima: smanjuje

“memory” celija, ukida AgP B ly, broj i funkciju Treg ly. P i IV ( i f ij ) d i d 375 / 2• Primena: IV (spora infuzija) u dozi od 375 mg/m2 u razlicitim intervalima prema klinickom odgovoru

• Fenomen “lize” prva doza moze da uzrkuje groznicu, hipotenziju, aritmije, bronhospazam koji bi mogli da budu

i i ihi i i i i k idiprevenirani antihistaminicima i k-steroidima.

Ponticelli C et Glassok R. Treatment of primary glomerulonephritis; Second edition, Oxford university press 2008.

Kljucne reci: Rituximab and glomerulonephritis = 203 rada

2001-2011. god.j

60

ci

50

60

U l th SLE liti

refe

renc

40Uglavnom u th SLE, vasculitisa

PostTX rekur. GN

Bro

j r

20

30

10

20

02001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011

Course of proteinuria after two doses of rituximab(RTX; 1 g each) Case report

Fervaneza FC et al. Idiopathic Membranous Nephropathy: Diagnosis andTreatment. Clin J Am Soc Nephrol 2008; 3: 905-919.

Rituximab therapy in idiopathic membranous nephropathy: a 2-year study (20 pts/24 moths)p p y y y ( p )

ADVERSE EVENTS in 12 pts

not serious !

Fervaneza FC et al . Clin J Am Soc Nephrol. 2010.;5(12):2188-98

Toksicni efekti rituximabaToksicni efekti rituximaba

1 “L sis” sindrom1. “Lysis” sindrom2. Infekcija (bakterijske ili oportunisticke j ( j p

virusne –herpes virus) 3 Toksican efekat na k srz ( Tr i Er )3. Toksican efekat na k. srz ( Tr i Er ) 4. Hipersenzitivne reakcije5. Trudnoca

Ponticelli C et Glassok R. Treatment of primary glomerulonephritis; Second edition, Oxford university press 2008.

Effect of Single-Dose Rituximab on P i Gl l Di (24 t )Primary Glomerular Diseases (24 pts)

10 2

r (m

g/dl

)

/day

)

6

8

1

1.5

Seru

m C

UP

(g

0

2

4

0

0.5

Baseline 1 month 3 months 6 months

0

Baseline 1 month 3 months 6 months

6

b (g

/dl)

3

5

6 MCD (10 pts)FSGS (4 pts)MN (4 pts)

Seru

m A

lb

0

1

2MPGN (1 pt) IgAN (5 pts)

Ad t i 1 t

Sugiura H et al Nephron Clin Pract 2011;117:c98-c105 Baseline 1 month 3 months 6 months

0 Adverse event in 1 pts

A case of recurrent immunotactoid glomerulopathy g p yin an allograft treated with rituximab

• Spherical microtubular deposits, with a diameter of 30-40 nm,with a diameter of 30 40 nm, • Sy. nephtoticuim, HTA, TBI in 40%, • High recurrence in Tx

Amyloid like glomerular

High recurrence in Tx but slower progession • 91% th no response Amyloid-like glomerular

deposits Congo red-negative 91% th no response

EM appearance of Congo Red-negative fibrillary GN

Sathyan S et al Transplant Proc. 2009 Nov;41(9):3953-5

UMESTO ZAKLJUCKA U S O JUC

Krajem 2011.