Aferesi terapeutica in Nefrologia - SIdEM · Aferesi terapeutica in Nefrologia Dario Roccatello,...
Transcript of Aferesi terapeutica in Nefrologia - SIdEM · Aferesi terapeutica in Nefrologia Dario Roccatello,...
Aferesi terapeutica in Aferesi terapeutica in NefrologiaNefrologia
Dario Roccatello, Mirella Alpa, Massimo Milan, Osva ldo Giachino
Dipartimento di Malattie Rare, Immunologiche, Emato logiche ed Immunoematologiche
Ospedali Torino Nord Emergenza G. Bosco e Maria Vitt oria eUniversità di Torino
Coordinamento Interregionale Malattie Rare del Piem onte e della Valle d’Aosta
APPLICATION OF APHERESIS TECHNIQUES FOR RENAL DISEASES
POSSIBLE MECHANISMS OF APHERESIS IN RENAL DISEASES
APPLICATION OF APHERESIS TECHNIQUES FOR RENAL DISEASES
Yokoyama H, Clin Exp Nephrol 2007
INDICATIONS FOR PLASMAPHERESIS IN RENAL DISEASES
Szczepiorkowski ZM, J Clin Apher 2007
1standard therapy2 conventional ther tried first3 inadequately tested4 no value in controlled trials
RECENT STUDIES OF PLEX IN AAV Casian and Jayne, Curr Op Rheumatol 2011
RANDOMIZED CONTROLLED TRIAL of METHYLPREDNISOLONE V ERSUS PLASMAPHERESIS for SEVERE RENAL VASCULITIS
TECHNICAL NOTES
Szczepiorkowski ZM, J Clin Apher 2010
Recommended therapy of AAV according to EULAR
Disease stage Recommendend treatment
Generalized (induction) Cyc oral or i.V. + GCsCyc oral: 2 mg/kg body weight/day; i.v.: 15 mg/kg (level 1°/1B, grade A) duration: 3-6 months or 6-9 pulses
according to CYCLOPS protocolGCs: prednisolone 1 mg/kg/day for 1 month, taper to < 15 mg/day within 3
monthsRituximab? Alentuzumab?
Severe (sCr > 500 umol/l) (induction) Standard therapy for generalized disease + plasma separationRituximab? Alemtuzumab?
Early systemic (induction) Mtx 15 mg/week s.c. or oral initially, increase to 20-25 mg/week + GC (level 1B grade B), Folic acid substitutionRituximab? Anti-TNF?
Maintenance of remission Aza 2 mg/kg/day (level 1B grade A)Lef 20 mg/day (level 1B grade B)Mtx 20-25 mg/week (level 2B grade B)*duration at least 18 monthsAnti-TNF?
Refractory, relapsing, persistent (induction) IVIG 2 g/kg for 5 daysRituximab 375 mg/m2 weekly for 4 weeksInfliximab 3-5 mg/kg i.v. one to two monthly MMF 2 g/day15-deoxyspergualin 0.5 mg/kg/day until nadir then stop until leukocyte recovery (six cycles)ATG 2.5 mg /kg/day for 10 days (adjusted to lymphocyte count)
Modified from Holle et al, J Autoimm., 2009
TECHNICAL NOTES
Szczepiorkowski ZM, J Clin Apher 2010
RPIgAN with >40% extracapillary proliferationRPIgAN with >40% extracapillary proliferation
EtàEtà
SexSex
MesiMesi Ialinosi Ialinosi glomerulareglomerulare
Crescents Crescents floridifloridi
Crescents Crescents scleroticisclerotici
Cr Cr µµµµµµµµmol/lmol/l
Proteinuria Proteinuria (g/24h)(g/24h)
AferesiAferesi
1616MM
0 (B)0 (B)2 (B)2 (B)16 (B)16 (B)
--10106565
909080801515
10101010--
884884212212522522
20.620.62.12.12.52.5
141488
4444MM
0 (B)0 (B)2 (B)2 (B)
6 6 24 (B)24 (B)
15153030
4545
40401010
2020
--2020
--
1061069797132132132132
440.80.82.62.64.24.2
1111
24 (B)24 (B) 4545 2020 -- 132132 4.24.2
6161FF
0 (B)0 (B)
2 (B)2 (B)
553030
70705050
----
636636265265
7.17.13.33.3
1414
3939MM
0 (B)0 (B)2 (B)2 (B)1212
35353030
50503030
----
238238230230HDHD
5.95.97.97.92.52.5
101055
5555MM
0 (B)0 (B)3636
-- 4040 -- 654654194194
5.75.722
1010
1818FF
0 (B)0 (B)120120
1515 8080 -- 265265371371
5.15.111
1818
Roccatello NDT,1995
PLEX in RPIgAN with > 60% florid crescents
Plasmaferesi nel trattamento della malattia da Ab anti-MB: sopravvivenza rene
75,0%
100,0%
’98
0,0%
25,0%
50,0%
75,0%
Johnson
Simpson
Hammer
smith
Aferesi
Controlli
’85RC ’82
C
’98nC
Plasmaferesi nel trattamento della malattia da Ab anti-MB: mortalità paziente
25,0%
50,0%
Aferesi
0,0%
Johnson
Simpson
Hammer
smith
Aferesi
Controlli
Hammersmith long-term (2001):1-year pt/renal survival: 100 & 95% if < 500 micromol sCr83 & 82 if > 500, but HD-independent65 & 8 if HD-dependent
TECHNICAL NOTES
Szczepiorkowski ZM, J Clin Apher 2010
TECHNICAL NOTES
Szczepiorkowski ZM, J Clin Apher 2010
TECHNICAL NOTES
Szczepiorkowski ZM, J Clin Apher 2010
TECHNICAL NOTES
Szczepiorkowski ZM, J Clin Apher 2010
TECHNICAL NOTES
Szczepiorkowski ZM, J Clin Apher 2010
Effetto clinico ed immunologico della PE nella CM
Trial non controllatati: 7
Miglioramento clinico: 55-87%
Roccatello et al, NDT, 1991
Filtrazione a cascata
Frazionamento del plasma su membrana semipermeabile
Rimozione
Filtrationcolumn
Rimozione semiselettiva di sostanze ad elevato peso molecolare
Relazione tra emivita e concentrazione γ-globuline
4
5
6
0
1
2
3
4
0 10 20 30
Concentrazione γ-globuline (mg/ml)
Curva di uptake epatico
Modificazioni della cinetica delle Ig: variazioni c oefficiente angolare
2
4
6
8
10
12
Ig Vena
2
4
6
8
10
12
Filtrazione a cascata
0
2
pre post
0
2
4
6
8
10
12
pre post
Immunoassorbimento
0
pre post
0
2
4
6
8
10
12
pre post
Bolo steroidi
*
Roccatello, Expert Reviews in Clinical Immunology, 2008
* PEG-IFN alfa 2a (180 ug/ weekly) or alfa 2b (1.5 u g/kg weekly) Ribavirine 1000 mg or 1200 mg/day, according to bod y weight ( ≤ or ≥ 75 kg)
DOUBLE FILTRATION PLASMAPHERESIS COMBINED WITH INTERFERON AND RIBAVIRIN THERAPY
RAPIDLY DECREASES THE AMOUNT OF HCV-RNA.
Ishikawa T, Ther Apher and Dial 2011
RCTs EVALUATING THE ROLE OF PLASMAPHERESIS IN MULTIPLE MYELOMA-ASSOCIATED RENAL FAILURE
(without biopsy and biological markers)Baweja S, J Artif Organs. 2011
Hutchison, 2007: 40 pts, 78% improvement RF if due to a cast-N and sFC dropped by >50%
Hutchison, 2009: 19 biopsy-proven cast-N pts treate d with high cut-off dialyzer (interrupted in 6 for infections), 13 became HD-ind ependent.
EuLITE trial ongoing
TECHNICAL NOTES
Szczepiorkowski ZM, J Clin Apher 2010
TECHNICAL NOTES
Szczepiorkowski ZM, J Clin Apher 2010
THROMBOTIC THROMBOCYTOPENIC PURPURA
Incidence: 0.37/100,000/year in the US Procedure TPE Raccomendation Grade 1A
Szczepiorkowski ZM, J Clin Apher 2010
Incidence: 0.37/100,000/year in the US Procedure TPE Raccomendation Grade 1A
# of reported patients: > 300
RCT 7 (301) CT 2 (133) CR 17 (915) CR 28 (48) Type of evidence I
TECHNICAL NOTES
Volume treated 1-1.5 TPVReplacement fluid plasma, plasma cryoprecipitate removed
A disintegrin and metalloproteinase with thrombospondin motif-13 (ADAMST-13) activity and anti-ADAMST-13 in 25 pts with acute refractory /relapsing idiopathic TTP treated with Rituximab mmediately following PE. All 25 pts attained complete clinical and labotatory remission in a medianof 11 days. No relapses were observed (Scully, BJH, 2006)
TECHNICAL NOTES
Szczepiorkowski ZM, J Clin Apher 2010
HUS
Typical HUS
Shigatoxin E Coli
(STEC)
Atypical HUS
(aHUS)
Haemolytic anemiaThrombocitytopeniaRenal impairment
High LDH(STEC)
Secondary aHUSS. Pneumoniae, HIV,H1N1
influenza, Malignacy,
Transplantation,
Pregnancy,
Sistemic diseases
Primary (Complement-)
aHUS
(also misleadingly
named non-post-
diarrheal HUS)
Undetectable haptoglobinlevel
10% bambini con aHUS > parte degli adulti
Neonatal Children (Pre-) Pregnancy
Congenital TTP (ADAMTS13
deficiency)
HUS secondary
S Pneumoniae
Ab anti
CFH
Based on age differential diagnosis TTP/HUS
Immune TTP(anti-ADAMTS13)
Neonatalperiod
Children6 m- 5 y
(Pre-)adolescents
Pregnancy
Post-partum
Methylmalonicaciduria
associatedHUS
STEC -HUSHereditary
ComplementaHUS
25% TTP pts have normal ADAMTS13 and 25% HUS have n o complement abnormalities
Adults
Complement activation
Short Consensus Repeats 1-4 binds to C 3b
SCR19-20 binds topolyanionic surface-bound C 3B
CFHmutation
CFImutation
MCPmutation
C3mutation
CFBmutation
Anti CFHAb
Decreased [C3] 50% 30% 2% 80% 100% 60%
Loirat and Fremeaux-Bacchi Orphanet Journal of Rare diseases 2011 6:60
Terapia: plasma exchange
• Terapia 1 scelta dal 2010
• Riduzione delle mortalità dal 50% al 25%
• Somministrazione con plasma di CFH,CFB,CFI, C3
• Rimozione di ab anti CFH
• Rimozione di CFH,CFI,CFB modificati• Rimozione di CFH,CFI,CFB modificati
• Preferito alla plasmaterapiaPlasmatherapy in Atypical Hemolytic Uremic Syndrome Chantal Loirat 1, Arnaud Garnier 1, Anne-Laure Sellier-Leclerc 1,Theresa Kwon Assistance Publique-Hôpitaux de Paris, Pediatric Nephrology Department, Université Paris-Diderot, Hôpital Robert Debré, Paris, Francea plasmaterapia
Terapia: plasma exchange
• Iniziare terapia appena possibile (massimo entro
Loirat and Fremeaux-Bacchi Orphanet Journal of Rare diseases 2011 6:60
Response to PEXCFH: 63%CFI: 25%MCP: 90% spontaneous remissions
frequent relaplesC3, CFB: 55%THBD: 85%Anti-CFH: 1rst line (plus immunosuppressants)
• Iniziare terapia appena possibile (massimo entro
24 ore) proseguendo quotidianamente
• All’inizio scambiare 1,5 VP (60-75 ml/Kg)
• Lo scambio deve essere plasma con plasma
• Se non possibile PEX iniziare con infusione di
plasma ( 10-15 ml/Kg)
• Se persistenza emolisi o mancata ripresa
funzionale (anche a PTL normalizzate) proseguire
con PE quotidiana o passare ad altra terapia
• Mutazione MCP: stop PEX; Mutazione CFH o CFI+
C3 o CFB: proseguire a priori indefinitamente
Successful Treatment of Atypical Hemolytic Uremic Syndrome with the Complement Inhibitor Eculizumab.
Jens Nuernberger1,*, Oliver Witzke1,*, Russell P. Rother, PhD2,*, Thomas Philipp1,*, Udo Vester1,*, Hideo
Baba1,*, Lothar Bernd Zimmerhackl3,* and Andreas Kribben1,*
Blood (ASH Annual Meeting Abstracts) 2008 112: Abstract 2294 © 2008 American Society of Hematology