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Rosanna CoppoTorino
Steroid resistant nephrotic syndrome:still a therepeutic challenge
minimal changeGN
mesangial proliferative GN
focal segmental glomerulosclerosis
IgMGN
Idiopathic Nephrotic Syndrome
In all these cases steroid resistance is the most strong predictor
of progression
corticosteroids
Nakayama, 2002
WWW.KDIGO.ORG
Clinical Practice Guideline for Glomerulonephritis
Kidney Disease: Improving Global Outcomes
WWW.KDIGO.ORG
4.1: EVALUATION OF CHILDREN WITH SRNS
4.1.1: We suggest a minimum of 8 weeks treatment with corticosteroids to define steroid resistance. (2D)
4.1.2: The following are required to evaluate the child with SRNS (Not Graded):
• a diagnostic kidney biopsy;
• evaluation of kidney function by GFR or eGFR;
• quantitation of urine protein excretion.
CHAPTER 4: STEROID-RESISTANT NEPHROTIC SYNDROME IN
CHILDREN
Podocytopathies
14 typesGenetically determined
steroid –resistant Idiopathic NS2-5%
of all the cases
Treatment of children and adults with
idiopathic steroid-resistant NS
ALKYLATING AGENTS
Cochrane Database Syst Rev 2010
Alkylating agents in idiopathic steroid-resistant NS in children
9 RCTs involving 449 children: RR of persistent NS• Oral Cyclophosphamide+P
vs Prednisone RR 1.01 (0.74-1.36)
• IV CPA vs oral CPA RR 0.09 (0.01-1.39)• Azathioprine+P
vs Prednisone RR 1.01 (0.77-1.32)
no significant effect of alkylating drugs
on RR of persistent NS
Treatment and outcome of children and adults with
idiopathic steroid-resistant NS
ALKYLATING AGENTS
CYCLOSPORIN
Kidney Disease: Improving Global Outcomes
WWW.KDIGO.ORG
4.2: TREATMENT RECOMMENDATIONS FOR SRNS
4.2.1: We recommend using a calcineurin inhibitor (CNI) as initial therapy for children with SRNS. (1B)
4.2.1.1: We suggest that CNI therapy be continued for a minimum of 6 months and then stopped if a partial or complete remission of proteinuria is not achieved. (2C)
4.2.1.2: We suggest CNIs be continued for a minimum of 12 months when at least a partial remission is achieved by 6 months. (2C)
4.2.1.3: We suggest that low-dose corticosteroid therapy be combined with CNI therapy. (2D)
CHAPTER 4: STEROID-RESISTANT NEPHROTIC SYNDROME IN
CHILDREN
Cyclosporin treatment decreasesglomerular utrafiltration coefficient
2,40
8,60
3,4
2,1
4,2
1,8
0
5
10
15
Saline CyA
Glomerula volume nl Kf (nl/min mmHg)Kl (ul/min mmHg cmH20)
CyA
Meyrier’s hypothesis:CyA is lipophilic and bind sto a lipidic complex associated to the slit diaphragm, limiting the protein leak
Synaptopodin (protein which stabilyzes cytosckeletal actin and is co-localyzes with
calcineurin)
Synaptopodin is instable and undergoes lysis due to cathepsin with disappearance of cytoskeleton
actin stress fibers
F actin
synactopodin
P ser / treo binding protein
The interaction between synaptopodin and serine/treonine binding protein maintains F-actin
stability, normal cytoskeleton structure and absence of proteinuria
Dephosphorylation
synactopodin
ser / treo BP
ser / tre
o protease
PKA, CaMKII
calcineurin
cathepsin
sinsin
sinCyclosporin
Cochrane Database Syst Rev 2010
Cyclosporin in idiopathic steroid-resistant NS in children
3 RCTs: 49 children:
RR of persistent NS
Cyclosporin (CyA) vs PL RR 0.64 (0.47-0.88)
Treatment of steroid-resistant NSCyclosporin A
Evidence-based recommendations
Treatment Level of evidence
Grade Comments
MCGL
Cyclosporin (at least 6 months)
4 D Possible benefit from pooled case series; no
significant benefit in RCT – small numbers
FSGSCyclosporin (at least 6 months)
1 A Beneficial
An example of CyA nephrotoxicity. Francois H, et al Am J Kidney Dis. 2007;49:158-61.
Renal tolerability of CyA is reasonably goodwhen the dosage is low
Meyrier A, Expert Opin Pharm 2005
Long Term CyA treatment in SRNSGE-ITALIAN STUDY Adult and Children
Ghiggeri 2004
• 55 steroid –resistant
NS treated with CyA
NS remission (partial or total): 20 patients
Mean follow-up: 81 months
Renal biopsy after 5 years of treatment:no tubular or interstitial fibrosis
Kidney Disease: Improving Global Outcomes
WWW.KDIGO.ORG
4.2: TREATMENT RECOMMENDATIONS FOR SRNS
4.2.1: We recommend using a calcineurin inhibitor (CNI) as initial therapy for children with SRNS. (1B)
4.2.1.1: We suggest that CNI therapy be continued for a minimum of 6 months and then stopped if a partial or complete remission of proteinuria is not achieved. (2C)
4.2.1.2: We suggest CNIs be continued for a minimum of 12 months when at least a partial remission is achieved by 6 months. (2C)
4.2.1.3: We suggest that low-dose corticosteroid therapy be combined with CNI therapy. (2D)
CHAPTER 4: STEROID-RESISTANT NEPHROTIC SYNDROME IN
CHILDREN
Kidney Disease: Improving Global Outcomes
WWW.KDIGO.ORG
4.2.2: We recommend treatment with ACE-I or ARBs for children with SRNS. (1B)
4.2.3: In children who fail to achieve remission with CNI therapy:
4.2.3.1: We suggest that mycophenolate mofetil (2D), high-dose corticosteroids (2D), or a combination of these agents (2D) be considered in children who fail to achieve complete or partial remission with CNIs and corticosteroids.
4.2.3.2: We suggest that cyclophosphamide not be given to children with SRNS. (2B)
CHAPTER 4: STEROID-RESISTANT NEPHROTIC SYNDROME IN
CHILDREN
Steroid therapy : different doses, different forms
Cyclosporin late response late and sustained effect,
cyclosporin dependancy, risk of toxicity Other calcineurin-inhibitors:
Tacrolimus
Steroid-, cytotoxic- and cyclosporin-resistant desperate NS:rescue therapy
22 children with steroid-resistant NS
(9 MCD, 11 FSGS, 2 MP)
TAC 0.1 mg/Kg/day (5-10 μg/ml TL)
TAC is an effective therapeutic modality for SRNS, including children non responsive to CP and CyA
Total remission10/13 resistant also to Cyclophosphamide(CP)
2/4 resistant also to Cyclosporine (CyA)Side effects:diarrhea and hypertension (3 withdrawn)
Mean time to remission : 60 days
Roberti I, Vyas S. Pediatr Nephrol 2010, 25: 1117-24
19 children with steroid-resistant NS
(10 FSGS, 5 other forms)
Long-term outcome of children with steroid-resistant nephrotic syndrome treated with tacrolimus
Complete remission:11/19 (58%) , partial in 6
Mean time to remission : 8 weeks
Remission sustained during follow-up in 58%.
Among FSGF remission 50% ,
in 40% non responders, ESRF.
41 children with steroid-resistant NS
TAC 0.1-0.2 mg/Kg or CsA 5-6 mg/Kg for 1 year
Alternative day steroids and ACE-i
(10 FSGS, 5 other forms)
At 6 mo Complete remission:TAC 85%, CsA 80%
RR for relapse after 1 year : OR 4.5 (TAC better)
Cosmetic negative effects in CsA only
Steroid therapy : different doses, different forms Cyclosporin late response late and sustained
effect,
cyclosporin dependancy, risk of toxicity
Other calcineurin-inhibitors:
Tacrolimus
Purine synthesis inhibitors:
Mycophenolate
Steroid-, cytotoxic- and cyclosporin-resistant desperate NS:rescue therapy
MMF and prednisone in steroid-dependent NS Bagga A Am J Kidney Dis 2003
19 Children previously treated with P, oral CP, and still cortico-dependent NS:
MMF 30 mg/Kg/day for 2 years associated with low tapering doses of Prednisone. FU: 18 months
75% reduction of relapses
After withdrawal relapse in 68% of the cases
Frequency of relapses from 6.6 to 2 each year p<0.0001:
MMF was effective as steroid-sparing agent
MMF in steroid-resistant NS
Author N cases
Regimen Efficacy
Day CJ (Wolverhampt, UK, NDT 2002)
7 adults
MMF (1 gx2) Complete remission 6/71/7 partial r.
Montané (Miami, US, Ped Nephrol 2003)
9childr.
MP pulses (15 mg/kg/week x 4-8)ACE-i/ARBMMF (250-500 mg/m2)
Proteinuria (6-24 months)72% below baselinep<0.01
Mendizabal S (Spain, Ped Nephrol 2005)
275 SRNS
no response to CP and CyAMMF (1200 mg/m2)
1/5 remissionRelapse after withdrawal.
Ulinski (Lyon, Ped Nephrol 2005)
94SRNS
CyA with GFR impairment:2g/1.73 m2
0/4 remissions
In FSGSMMF should be used for > 6 months,
No RCT is available.
The rate of relapse is high.
Kidney Disease: Improving Global Outcomes
WWW.KDIGO.ORG
4.2.2: We recommend treatment with ACE-I or ARBs for children with SRNS. (1B)
4.2.3: In children who fail to achieve remission with CNI therapy:
4.2.3.1: We suggest that mycophenolate mofetil (2D), high-dose corticosteroids (2D), or a combination of these agents (2D) be considered in children who fail to achieve complete or partial remission with CNIs and corticosteroids.
4.2.3.2: We suggest that cyclophosphamide not be given to children with SRNS. (2B)
CHAPTER 4: STEROID-RESISTANT NEPHROTIC SYNDROME IN
CHILDREN
Plasmapheresis
Steroid-, cytotoxic- and cyclosporin-resistant desperate NS:rescue therapy
sporadic case reports
Permeability factor (PF)V.Savin 1993
PF is a small anionic protein that binds to Prot A and has analogies with Immunoglobulins
Plasmapheresis and protein A immunoadsorption
Dantal et al (N Engl, 1994) In native and in recurrent FSGS in grafted kidneys:
• Effect often limited in time, with relapse at withdrawal• High cost / often limited benefits• In cases with antiproteinuric response the
progression to ESRF is only partially limited
Recurrence of FSGS on transplanted kidney
Plasmapheresis orImmunoadsorbanceon A Protein+ cyclophosfamide:70% reduction in proteinuria
Lyon and Miami Protocol
B cellsas new target
for NS treatment?
Steroid-, cytotoxic- and cyclosporin- resistant NS:sporadic case reports of
rescue therapy
Anti-CD 20 chimeric MoAbRituximab
Rituximab is a
Chimeric Monoclonal Ab:
Mouse IgG variable region
directed against CD20 Ag
+
Human IgG1 constant
region
A review of the current use of rituximab in autoimmune diseases
Gurvan HM Int Immunopharmacol 2008 Nov
Pharmacological effects: B lymphocytes depletion
Reduced expression of
activated T cell markers
T lymphocytes and NSHodgkin’s diseaseAllergyViral infectionsIn vitro evidences Shaloub’s hypothesis: permeabilizing T lymphokine
Permeability Factor (Ig part?)B cells activated in relapse
B and T collaboration
Francois H, Daugas E, Bensman A, Ronco P.Unexpected efficacy of rituximab in multirelapsing minimal
change nephrotic syndrome in the adult Am J Kidney Dis. 2007;49:158-61.
Rituximab
375 mg/m2 x4
persistent remission
Results
• Always effective in 15/15 proteinuria-free patients
• Remission was induced in 3/7 NS• In 19/22( 85%) one or more concomitant
immunosuppressive treatment was stopped
RTX was repeated in 12 patients who responded,
when CD19 count was >1% of total lymphocytes
Collaborative study (London, Tokyo, Toronto, Turin)
G1) steroid-dependent NS : (28 cases)Complete remission: 61%
G 2) steroid-resistant NS (27 cases)Complete remission: 22%
G3 post transplant recurrrence (15 cases)Complete remission: 40%
Side effects 26%Skin rash,bronchospasm, hypotension
Rituximab used in > 500.000 subjects
Adverse events:
- Allergic reactions, anti chimeric Antibodies.
0
5
10
15
20
25
30
35
% HA
CA po
sitive
0 3 6 9 12
Rituximab toxicity and adverse events:
progressive multifocal leukoencephalopathy (PML)
in 2 cases of SLE and one of RA
treated with multiple drugs , including Rituximab
2 SLE, 1 RA, 2 autoimmune pancytopenia/thrombocytopenia7 stem cells Tx, 26 purine analogues, 39 alkylating agents
52 lymphoproliferative disorders
The emerging role of podocytes
F actin
synactopodin
P ser / treo binding protein
The interaction between synaptopodin and serine/treonine binding protein maintains F-actin
stability, normal cytoskeleton structure and absence of proteinuria
Dephosphorylation
synactopodin
ser / treo BP
ser / tre
o protease
PKA, CaMKII
calcineurin
cathepsin
sinsin
sin
protease inhibitors?
New treatments forNephrotic syndrome
transcription
viral proteins
viral capsids PROTEASE INHIBITORS
PROTEASE INHIBITORS
ANTI-RETROVIRAL DRUGSHIV
• 6 males, 2 females• Previous history of NS: 7.2 ± 4.2 years
3 primary SRNS, 3 secondary SRNS2 SDNS
• Previous treatments: – Steroids, ACTH (8/8)– Cyclophosphamide (4/8)– Cyclosporine A (7/8), Tacrolimus (5/8), MMF (3/8)– Plasma exchange (3/8)– Rituximab (4/8)
• Median age at SAQ start-up : 13.5 (7-38) years• Median duration of treatment: 14.7 (6-68) months
8 patients in treatment with saquinavir 30 mg/Kg/day
Increase in Cyclosporine A and tacrolimus blood levels
CyP450pGpMDR2/3
SAQ is metabolyzed by isoenzyme CYP3A4: modifies CyA and TAC metabolism
SAQ is substrate and inhibitor
Pharmacokinetic interactions
drug interaction between saquinavir and calcineurin inhibitors
• Cyclosporine A: 2 mg/kg/day(vs 5 mg/kg/day before SAQ)to maintain a blood levels of 100 ng/ml
• Tacrolimus: 0.01-0.06 (median 0.018) mg/kg/day(vs 0.1 mg/kg/day before SAQ)to maintain a blood levels of 3-5
Medium dosage of calcineurin inhibitors administered together with saquinavir
Pre-SAQ Post-SAQ0
25
50
75
100
meanreductionof 56%
%
12 months before SAQ Last 12 months with SAQ0
5
10
15
20
25
30
35
p=0.03
Pre-saquinavir Post-saquinavir
Pre
dn
iso
ne
mg
/kg
/mo
nth
Medium dosage of prednisone:
8.4mg/kg/month
Significant decrease in cumulative steroid dosage
Medium dosage of prednisone:
25.2 mg/kg/monthMean
reduction of 63%
Nuclear binding of NF-kB p50- p65 in immortalized human podocytes activated by LPS without or with addition of SAQ 10 and 20 µM.
Nuclear binding of NF-kB p50, p65 in immortalized human podocytes activated by TNFα with or without additionof SAQ10 and 20 µM.
• The protease inhibitor SAQUINAVIR
provided with proteasome inhibitor activity:
1/2 primary SRNS
5/5 SDNS or secondary SRNS
• This drug was active when associated with calcineurin inhibitors, which had to be reduced to less than one third of the original dose to obtain safe blood levels.
Conclusions
Infrequent relapsers
saquinavir benefits:hypotheses
Proteasome-inhibitor activity:
NF-kB hyperactivity inhibition of in circulating mononuclear cells with decrease synthesis of a permeability factor (IPS downregulation)
Proteasome-inhibitor activity:
NF-kB hyperactivity inhibition in podocytes with foot process rearrangement.
Direct impact on podocyte protein synthesis
saquinavir benefits:hypotheses
Combined effect with low doses of CNI and prednisone
NF-kB target forSaquinavir (protease inhibitor)
Glucocorticoids (GCR binding to p65)CNI (non competitive inhibitors of proteasome
& ubiquitinylation)
saquinavir benefits:hypotheses
anti retroviral drug:antiviral beneficial effect in NS?
A rescue therapy may be triedeven in steroid resistant NS
CsA, TAC (MMF)PERituximab
new approaches :Protease inhibitorsAntifibrotic drugs?
Thank you Grazie
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