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HOW TO BUILD A REFERENCE CENTER
Giuseppe Remuzzi Mario Negri Institute for Pharmacological Research
June16–19,2016Amsterdam,Netherlands
KDIGO
CASE REPORT
On August 15, 1988 B.L, a 21-year-old-man was admitted to the Unit of Nephrology of Bergamo Hospital because of: - fever - jaundice - confusion Laboratory findings - Hct: 27% - LDH: 2343 I.U./L - Platelet count: 27 x 103/µl Diagnosis: TTP Treatment: Plasma exchange Outcome: Full recovery of the acute episode
- aphasia - migrating paresthesias - visual abnormalities
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KDIGO
Since August 1988
Almost 2-hundreds (monthly) recurrences of TTP Recovery of acute episodes with plasma therapy Progressive renal function deterioration Started chronic dialysis (March 3, 2001) Persistency of monthly recurrences with predominant gastrointestinal symptoms and occasional gastrointestinal bleeding
CLINICAL COURSE
3
KDIGO
PLASMA EXCHANGE vs INFUSION IN CHRONIC RELAPSING TTP Pl
atel
et c
ount
(x 1
000/
mm
3 )
0 30
200
0 30
200
1 3 6 9
0 30
200
0 30
200
0 30
200
1 3 6 9 0
30
200
1 3 6 9 days Plasma exchange Plasma infusion
Ruggenenti et al., Am J Kidney Dis, 1993 4
KDIGO
5
Plat
elet
cou
nt (x
100
0/m
m 3 )
0
30
200
0
30
200
1 3 6 9
0
30
200
0
30
200
1 3 6 9
0
30
200
1 3 6 9 days
Plasma removal Plasma infusion
0
30
200
Ruggenenti et al., Am J Kidney Dis, 1993
PLASMA INFUSION vs REMOVAL IN FAMILIAL AND RECURRENT TTP
KDIGO
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KDIGO
1992
KDIGO
8
KDIGO
9 Niguarda, S.Raffaele, Policlinico, Istituto Tumori, Besta, S.Matteo
KDIGO
10
2001 à13 Presidi 2015 à 38 Presidi
Centro di coordinamento
REGIONAL NETWORK FOR RARE DISEASES
≤ 8081 - 149≥ 150
Number of diseasesserved by Reference centers
KDIGO
11
13
23
26 29
31 31 32 34 35 35
38 38
0
5
10
15
20
25
30
35
40
2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016
+ 484- 159
+ 91- 51
+ 76- 41
+ 69- 31
+ 170- 23
+ 21- 3
+ 84- 6
+ 11
+ 6
+ 19 - 4
- 57
+ New endprsments - Withdrawal
N° Reference centers
REGIONAL NETWORK FOR RARE DISEASESEVOLUTION OF REFERENCE CENTERS
KDIGO
12
0
2
4
6
8
10
12
14
16
18
< 0,002% Tra 0,002% e 0,004% Tra 0,005% e 0,01% > 0,01%
No.
Ref
eren
ce c
ente
rs
Rare Disease Prevalence
REGIONAL NETWORK FOR RARE DISEASESDISEASES THAT ARE LESS RARE HAVE HOWEVER MORE REFERENCE CENTERS
KDIGO
Regional Network for Rare Disease Working Group
• Goals– The Working Group establishes uniform strategies for the
reference centers to pursue prevention, surveillance, diagnosis and treatment of rare diseases
• The Working Group is composed by rappresentatives of– Region– Reference centers– Coordination Center– Local health authority– Patient associations
13
KDIGO
943
687
539
747
606 596
1263
1937
1644
1500
1324
1088 1145
1035
2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015
February 29, 20081st Rare Diseases Day
COORDINATION CENTER: CONSULTING ACTIVITY
14
KDIGO
15
0%
10%
20%
30%
40%
50%
60%
70%
80%
2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014
Pazienti e FamiliariOperatori Sanitari
COORDINATION CENTER: CONSULTING ACTIVITY
KDIGO
Regional Networks evolution in Italy
2001 ...200716
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PATIENT DISTRIBUTION BY AGE AND GENDER
Lombardypopula-on 9.973.397*
AllRDcases 54.647
Dieases 291
Prevalence 548/100.000
*ISTAT Italian Population Census – January 1st, 2014
KDIGO
Diagnostic , Therapeutic and Social Care Pathways (PDTA)
• 632 health care professional were involved • 31 reference centers• 33 patient associations
• 110 PDTA were prepared
• They cover approximately 72 – 87% of rare disease recorded in Lombardy
Since 2012 the Regional Network has promoted the development, through conferences of experts, of shared pathways for the diagnosis, treatment and social assistance to patients with rare diseaseThese pathways are intended to offer the best quality of care whereby optimizing the use of resources
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KDIGO
PDTA ARE AVAILABLE AT THE COORDINATION WEBSITE
0
2000
4000
6000
8000
10000
2011 2012 2013 2014 *
* dal 30 marzo 201119
KDIGO
HOW THE REGIONAL NETWORK IS EVALUATED BY THE PATIENTS
"Malattie rare: rilevazione dei bisogni assistenziali e definizione di misure a sostegno". Decreto n. 7771 del 11.09.2012, Direzione Generale Sanità, Regione Lombardia Éupolis Lombardia, Edizione: aprile 2014
1 = per nulla soddisfatto
0 1 2 3 4 5
5 = molto soddisfatto
Assistenza socio-sanitaria globalmente ricevuta
Presidio di riferimento per la malattia
Medico di Medicina Generale o Pediatra di Libera Scelta
Distretto socio-sanitario/Azienda Sanitaria Locale (ASL)
Servizi sociali (del Comune o di soggetti delegati)
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KDIGO
EXPERTISE AND ORGANIZATIONAL SUPPORT FOR CLINICAL STUDIES
IMPROVE KNOWLEDGE AND POSSIBILITY OF TREATMENT IN RARE
DESEASES
RESULTS DIFFUSION
STATISTICAL ANALYSIS
STUDY MONITORING
STUDY DEVELOPMENT
REGULATORY ASPECTS
STUDY DESIGN
RESEARCH AIM
DEFINITIONEUROPEAN SCHOOL FOR RARE DISEASESThe Center is the site of active cultural activity at several levels, aimed to both spec ia l i s ts and t ra in ing hea l th professionals
Regular courses for training in clinical research are addressed to:
- Medical doctors- Registered nurses- Statisticians- Monitors- Bioengineering- Epidemiologists- Informatics
21
KDIGO
22,765
221992 - 2015
KDIGO
23
3 KDIGO
24
Ryan
24
Prevalence: 1,6/1,000,000 persons
KDIGO
BergamoTrento
Padova
TrevisoVicenza
ParmaGenovaTorino
Pavia
Milano
VareseMonza
Brescia
Firenze
Roma
Foggia
BariSalerno
Reggio CalabriaPalermo
Cagliari
Sassari
UK9 cases
USA58 cases
Argentina 23 cases
Belgium 1 case
Israel14 cases
Portugal11 cases
Canada 4 cases
Switzerland 22 cases
South Africa2 cases
Germany 19 cases
Denmark 3 cases
Saudi Arabia4 cases
Czech R.11 cases
Esthonia1 case
Serbia 5 cases
Italy765 cases
Greece 4 cases
Australia14 cases
Malaysia 2 cases
Turkey8 cases
IRAN49 cases
Spain 5 cases
Poland13 cases
Russia6cases
UAE1case India
5casesJapan2cases
Chile3cases
Par-cipa-ngCenters
HUS/TTPpa-entsItaliancasesForeigncases
180
1160780380
INTERNATIONALREGISTRYOFHUS/TTP
09/2015
Brazil2cases
Croa-a2cases
25
KDIGO
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1 2 3 4 9876510 11 13 1412 15 16 17 18 19 20
1 2 31 2 3
CFH76 mutations
CFB5 mutations C3 12 mutations
MCP 28 mutations
CFI 23 mutations
Bergamo
Newcastle
Madrid
Toulose
Paris
TM 6 mutations
2
3
4
1KDIGO
27
COMPLEMENT ABNORMALITIES IN 272 PATIENTS
Factor H
MCP
Factor H ab
C3
Factor I
TM
Factor B
Combined
?
0 10Cumulation incidence (%)
25
20 504030
10
7
7
8
1
35
3
Noris et al. J Am Soc Nephrol, 2010
4
T30Nfs10XG1194DG1194DR1210CR1210CR1210CR1215Q N767Kfs7XP968fs947XS1191L V1197AR341H
1234567
123
12
SIIFIIS FSI IF
H183RI340TE554V
G1094RR161W
Cohort CFH MCP CFI C3#I208Y F242C F242C Y29X
C35Y and R59X C35Y and R59X
R103Q
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The patient and the unaffected mother and brother carry a a very rare genomic rearrangement between CFH and CFHR1 genes generating heterozygous CFH/CFHR1 hybrid protein in which SCR 1-19 are derived from CFH and SCR 20 from SCR 5 of CFHR1 by non allelic homologous recombination
ATYPICAL HEMOLYTIC UREMIC SYNDROME ASSOCIATED WITH A HYBRID COMPLEMENT GENE
CFH CFHR3 CFHR1Deletion
CFH/CFHR1 fusion protein
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
1 2 3 4 5 1 2 3 4 5
5
Valoti et al., JASN, 2015
KDIGO
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LONG-TERM OUTCOMES FOR aHUS PATIENTS
CFH mutation
Patie
nts
free
of e
vent
s D
eath
or E
SRD
(%)
100
80
60
40
20
00 2 4 6 8 10 12
Follow up (years)
Noris et al., C J Am Soc Nephrol, 2010
Tx?
KDIGO
30 30
KDIGO
Rat kidney reperfusion
ORTHOTOPIC KIDNEY TRANSPLANTATION IN RATS
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32
MCP
C3
Factor I
Factor H
Factor B
KDIGO
EFFECTS OF 52 WEEKS OF ECULIZUMAB THERAPY IN PATIENTS WITH PLASMA DEPENDENT OR PLASMA RESISTANT ATYPICAL HUS
Dependent(n = 20)
Persistent remission
Need for plasma therapy
Serious treatment-relatedadverse events
Licht et al., J Am Soc Nephrol, 2011Greenbaum et al., J Am Soc Nephrol, 2011Legendre et al., N Engl J Med, 2013
Resistant(n = 17)
17
0
0
15
0
0
33
KDIGO
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Ryan
35
330,000 euro per patient per year
460.000
KDIGO
Rare diseases and effective treatments: are we delivering? Lucio Luzzatto, Carla E M Hollak, Timothy M Cox, Arrigo Schieppati, Christoph Licht, Helena Kääriäinen, Giampaolo Merlini, Franz Schaefer, Steven Simoens, Luca Pani, Silvio Garattini, Giuseppe Remuzzi
28 February 2015
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KDIGO
37
Ogni 15 giorni per sempre? KDIGO
C3b
C3
C3b
C3a
Endothelial cell Glycosaminoglycans
iC3b C3b
CFB
Surface bound C3 convertase
C3b Bb
CFB
Bb
CFI
iC3b
CFI
CFH
C5b-9
C5 convertase
C5 C5a
20
Alternative pathway activation (spontaneous hydrolysis, bacteria, viruses)
Fluid phase C3 convertase 20
ALTERNATIVE PATHWAY ACTIVATION IS IMPAIRED IN SOLID BUT NOT IN FLUID PHASE
38
KDIGO
Normal serum
C5b-9
39
ADPC3b C3b
Normal serum
Resting endothelium Activated endothelium
Acute aHUS serum
C5b-9
ADPC3b C3b
aHUS serum in remission Asymptomatic carrier serum
Resting endothelium Activated endothelium
C5b-9C5b-9 C5b-9C3b
C3b C5b-9C5b-9
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- Control or aHUS serum
Static incubation4 hours
C5b-9 depositionHMEC-110 min
Resting
- anti-C5b-9 Ab staining- Confocal microscopy
0
1000
2000
3000
4000
5000
6000
7000
8000
*
C5b
-9 fo
rmed
(pix
el2 )
aHUS
Noris et al, Blood, 2014
Control (n=4)
Acute (n=7)
Remis (n=7)
Resting endothelium 10,000
Control aHUS
8,000
6,000
4,000
2,000
0aHUS +
Eculizumab
C5b
-9 fo
rmed
(pix
el2 )
Activated endothelium
KDIGO
KDIGO
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KDIGO
43
I
I I
S1191L mutation in CFH
39 yrHD
41 yr
I I
I
68 yr
c.3572 C>Tp.Ser1191Leu
A 1-year old child was admitted with familial aHUS and a heterozygous loss of function mutation in complement factor H gene (3645C>T) and developed aHUS at 6 months of age
April 2007
1 yr
KDIGO
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DIALYSISPLASMA THERAPY
ECULIZUMAB
300 mg
KIDNEY TRANSPLANTECULIZUMAB
0
50
100
150
200
250
300
0 10 20 30 40 50 60 70 80PLAT
ELET
CO
UN
T (1
03/m
icro
liter
)
months90
Pediatric case
100 110
Kidney Tx
600
Eculizumab (mg)
1 7
300 600
1
300 300
2 months3 4 514 days0
300 300 300 300 300 300 300 300
Aug 19, 2011 – 5 years of age
KDIGO
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DIALYSISPLASMA THERAPY
ECULIZUMAB
300 mg
KIDNEY TRANSPLANTECULIZUMAB
0
50
100
150
200
250
300
0 10 20 30 40 50 60 70 80PLAT
ELET
CO
UN
T (1
03/m
icro
liter
)
months
post-Ecu300
0
2000
4000
6000
8000
C5b
-9 fo
rmed
(pix
el2 )
90
Pediatric case
100 110
post-Ecu600
post-Ecu600
600 mg
ECULIZUMAB
Post-Ecu 600
Noris et al., Blood, 2014
165 418Eculizumab levels microgr/ml
CH50(normal range 79-187 Ueq/ml) 72 3 3 6 6
KDIGO
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600 mgDIALYSISPLASMA THERAPY
ECULIZUMAB
300 mg
KIDNEY TRANSPLANTECULIZUMAB
0
50
100
150
200
250
300
0 10 20 30 40 50 60 70 80PLAT
ELET
CO
UN
T (1
03/m
icro
liter
)
months
0
2000
4000
6000
8000
C5b
-9 fo
rmed
(pix
el2 )
90
Pediatric case
100
ECULIZUMAB
LIVER TRANSPLANT
post-Tx liverEcu
110
pre-Tx liverEcu
Sept 18, 2014 – 8 years of age
post-Ecu300
post-Ecu600
post-Ecu600
EcuSTOP
EcuSTOP
KDIGO
Bergamo Trento
Padova
Treviso
BolognaGenova
Torino ParmaMilano
Monza Brescia
Firenze
Roma
BariNapoli
USA2 cases
Argentina 2 cases
Israel4 cases
Portugal 1 case
Switzerland 2 cases
Czech R. 1 case
Italy204 cases
Turkey1 case
IRAN3 cases
Chile 1 case
Participating Centers
Ig-MPGN/C3G patients Italian cases Foreign cases
50
227 204 23
REGISTRY OF MPGN/C3G
09/2014
http://negribergamo.marionegri.it/
Russia 1 case
Modena
Como
Messina
Bolzano
Perugia
Germany 1 case
UK1 case
Poland1 case
France1 case
Croatia1 caseKDIGO
EAGLE Study Evaluating the Morphofunctional Effects of
Eculizumab* Therapy in Primary Membranoproliferative Glomerulonephritis:
A Pilot, Single Arm Study in 10 Patients with Persistent Heavy Proteinuria
and low C3 levels and high sC5b9 levels (>1000 ng/ml)
Elena Mondo, Piero Ruggenenti, Erica Daina, Marina Noris, Elena Bresin and Giuseppe Remuzzi
Unit of Nephrology, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy Clinical Research Center for Rare Diseases “Aldo e Cele Daccò”, Mario Negri Institute for Pharmacological Research, Bergamo, Italy
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* 900 mg weekly for four infusion and maintenance phase 1200 mg at week 5; then 1200 mg every 2 weeks for 1 years
KDIGO
BergamoTrento
Padova
Treviso
TorinoParma
Milano
Firenze
Roma
Foggia
BariNapoli
USA2 cases
Greece1 case
Romania2 cases
Italy235 cases
Turkey2 case
IRAN20 cases
Participating Centers
SRNS patientsItalian casesForeign cases
32
274235 39
REGISTRY OF SRNS
Palermo
Pisa
Germany1 case
Belgium6 cases
Bosnia1 case
Sweden1 case
Spain1 case
Trieste
Gorizia
Ancona
Chieti
Reggio Calabria
Catanzaro
INDIA1 case SENEGAL
1 case
http://www.marionegri.it
07/2015
49
THE REGISTRY OF STEROID RESISTANT NEPHROTIC SYNDROME
KDIGO
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J Am Soc Nephrol, 2014
KDIGO
DERIVATION OF HUMAN iPSC-DERIVED PODOCYTES
Mature podocytes
d1d0 d4Plating
Mesoderm induction
Renal precursors
d6Reprogramming* by 4 factors:
- Oct4- Sox2- Klf4 - cMyc
iPS cells
PBMC
51
d13
Synaptopodin/DAPI Nephrin/DAPI
KDIGO
Synaptopodin WT-1
KDIGO
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In vitro15 days
KDIGO
Adaptative Designs: Examples
Gupta et al, J Clin Epidemiol 2011
Ranking and selection designs - “Pick-the-winner”, “drop-the-losers” designs are used for
treatment/dose selection for a subsequent randomized study)
Internal pilot designs - The sample size is calculated during the pilot phase and patients
of the pilot study are maintained in the subsequent trial
Sequential designs - Continuous sequential analyses are planned with pre-set
stopping criteria
Response-adaptative randomization designs - Possibility to adapt the study design according to preliminary
outcomes
54
KDIGO
BALLS-IN-URN RESPONSE-ADAPTATIVE RANDOMIZATION DESIGNSProbability of being allocated to experimental therapy 50% 66% 75%
Experimental
Conventionall
• Black balls are added whenever a patient assigned to experimental therapy survives or one allocated to conventional therapy dies
• White balls are added whenever a patient assigned to experimental therapy dies or one allocated to conventional therapy survives
• The process continues until a preset stopping criterion is metGupta et al, J Clin Epidemiol, 201155
KDIGO
330 56
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5 57
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These slides belong to Giuseppe Remuzzi, M.D.
Mario Negri Institute for Pharmacological Research, Bergamo, Italy.
Using these slides is only authorized when mentioning the source
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