steroid resistant nephrotic syndrome (focus on...
TRANSCRIPT
Steroid Resistant Nephrotic syndrome (focus on treatment)
Markus J. Kemper
Idiopathic Nephrotic syndrome: Minimal Change or FSGS?
steroid-sensitive (90%)= Minimal Change NS -no biopsy
-normal kidney function -relapses,steroid-ependency
steroid-resistant (10%)= -biopsy & genetic testing -risk of ESRD - relapse after KTx (in
immune mediated FSGS) -Cave: Membranous GN and others
Idiopathic Nephrotic syndrome
Idiopathic NS= includes both Minimal Change NS and FSGS
• Histological diagnosis
• Immune mediated
• Genetic causes (structural defects of podocyte) • AD/AR
• syndromic
Prognosis of SRNS/FSGS
• Severe nephrotic syndrome
• Treatment resistant
• Immune mediated SRNS/FSGS
• Risk of progression to ESRD if no response to tretment
• Risk of recurrence after transplantation
• Fanilial/Gentic SRNS/FSGS
• Progression to ESRD
• Treatment?
• No recurrence after renal transplantation
Cave: do not give steroids (or consider early additional treatment or consider early biospy or genetic testing)
• Take medical history
• Physical examination
Age and NS
0 3 6 9 12 15 18
Genetic causes
•NS (Finn. Type)
•Podocin mutations
•WT1 mutations
Postinfektious GN
Idiopathic NS
•Minimal Change >
•FSGS
Glomerulonephritis
•SLE
•FSGS
•Membranous GN
•MPGN
Age (years)
Physical examination
Primäre Glomeruluopathien
MCNS
Steroids +
Cyclo-phosphamide +/-
Mycophenolate +
CSA/Tac ++
Immunosuppression in
Nephrotic Syndrome
Primäre Glomeruluopathien
MCNS FSGS
Steroids + (+)
Cyclo-
phosphamide +/- (+)
Mycophenolate + (+)/-
CSA/Tac ++ +
Immunosuppression in
Nephrotic Syndrome
Treatment of steroid-resistant NS
• (Pulse) steroids
• Cyclophosphamide
• MMF
• Calcineurin inhibitors
• Rituximab
• Future treatments
Primäre Glomeruluopathien
Summary Immunosuppression in
SR Nephrotic Syndrome
Van Husen & Kemper 2011
(Pulse) steroids
• So called „Mendoza“ Protocol • 30 mg/kg • Good remission rates (2/3) • Combined treatment with
cyclophosphamide
First Line Tx
Add On
Cyclophosphamide
Various results
Less successful than in steroid responsive NS
Rennert 1999, Gulati 2000: response to iv cyclosphosphamide superior than oral cylophosphamide
How about MMF?
First Line Tx
MMF added to CSA
Methylprednisolone, cylophosphamide and MMF in SRNS: resumee
Mostly uncontrolled series
Iv MP: standard in many countries (to exclude late response)
MMF & cylophosphamide various results
MMF less toxicity, trial worthwile but not as first-line treatment
Cyclosporine (Tacrolimus) in SRNS
Study Complete Response
Niaudet 1994 40%
NIH Study 45.8%
Ehrich 2007 (+iv MP)
84%
Hamasaki 2013 85.7%
Etc.
Klaassen et al, 2015
Klaassen et al, 2015
Renal function in SRNS on CSA
Immune mediated vs. Genetic forms (----)
New kid on the block: Rituximab
X
Rituximab in primary FSGS Bagga 2007
Kemper et al, 2014
Humanized anti-CD20
Recurrent FSGS after KTx:
Effect of RTX
Yabu et al, AJT 2008 Apeland et al, NDT 2008
Rituximab in FSGS after KTx
Summary Rituximab in SRNS/FSGS
• Works less well in SRNS/FSGS patients than SSNS/MCNS. Data mainly from smaller case series.
• Problem: Inconsistencies of definitions
• Primary vs. secondary steroid resistance
• (partial/complete) response to calcineurin inhibitors etc.
• Individual patients seem to benefit , before and after KTx
• Rituximab as Rescue? (Cave publication bias!)
• Controlled trials (e.g. also in earlier stages of FSGS) seem mandatory
• Ofatumumab better?
Future directions?
Galactose
Abatacept
….
How should we treat genetic forms of
steroid-resistent nephrotic syndrome?
SRNS, girl, 4 weeks of age
Klaassen et al, 2015
Summary: Treatment of steroid-resistant nephrotic syndrome
• Improved diagnosis and outcome
• First-line treatment: calcineurin-inhibitors
• Own practice in patients with full remission: discontinuation (tapering)
• Second-line treatment MMF and Rituximab
• ACE inhibitors for all
• Genetic forms: trial of CNI, but stop, if no response
• Other biologicals? Statins? Plasmapheresis?
Treatment of SRNS
MMF
CSA, Tacrolimus
Rituximab
Other
biologicals?
Pulse steroids