Mesto drugih savremenih Mesto drugih savremenih imunosupresiva u lecenju nefrotskog sindroma Sanja Simic Ogrizovic Nefroloska klinika, KCS Nefroloska klinika, KCS Medicinski fakultet, Beograd
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.