Journal Club - Biologics for Proteinuric Kidney Disease
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Transcript of Journal Club - Biologics for Proteinuric Kidney Disease
Biologics in Proteinuric Kidney DiseaseJournal Club Dec 2013
What will I cover?
• 2 Papers– Nephrotic Syndrome– Biological therapies where
‘conventional’ treatment has failed
• Implications for Future Treatment Strategies / Funding etc.
Glomerular structure facilitating ultrafiltration
The Glomerular Filtration Barrier
The Podocyte – ‘Function follows Form’
• Podocytes adapt to changes in mechanical stress and molecular signals
• This relies on:– Intact Actin Skeleton– Intact Slit Diaphragm Configuration– Intact ‘Scaffold’ Proteins
Ronco P. JCI. 2007 117(8):2079-82.
Failure of the Filtration Barrier in Nephrotic Syndrome
Case from Practice55 year old manPresented with nephrotic syndrome
– 15 grams proteinuria– Albumin 17g/L at presentation
Biopsied– Minimal Change Disease
Started on Prednisolone 80mg daily– Albumin 17 → 32g/L but proteinuria
persisted– Started on Perindopril + uptitrated
Clinical Course
• Prompt relapse in hypoalbuminaemia when steroids cut below 20mg/day– Escalated to oral cyclophosphamide for
6 months• 2 LRTIs and one episode of transient AKI
needing to stop ACEi for a bit
– Albumin slowly rose to 34 g/L maximum– Partial response to proteinuria (ACR
800)
• Further relapse in hypoalbuminaemia 2 months post cessation of cyclophosphamide– (Gained 17 kilos in 1/52!)
• High dose steroids work at cost to:– Blood Sugars / Weight Gain– Skin Problems
• Debate on how to proceed:– IV Cyclophos vs. Oral Tacrolimus– Opted for fortnightly doses of IV cyclophosphamide
for 3 months– Still heavily nephrotic, serum albumin <20g/L
Paper 1
Rituximab
• Chimeric Monoclonal Antibody– Usual Target – CD20 expressed on B-lineage
cells and a small population of T cells– Strong evidence for use in immune
depletion for primary membranous nephropathy
2006– Rituximab found to bind to podocytes,
despite no evidence of CD20 expression– Binds to amino acid sequence found on the
protein SMPDL-3b
Relevance of SMPDL-3b to Proteinuric Kidney Diseases
• SMPDL-3b depleted podocytes seen in post re-perfusion biopsies who developed recurrent FSGS
• Treatment with rituximab led to an increase in SMPDL-3b expression and subsequent reduction in proteinuria– Proposed mechanism – stabilise SMPDL-
3b + stops downstream signallingFornoni et al 2011
Outline of Study – Few Points• Open label prospective trial
• 25 patients fulfilled criteria for ‘steroid dependent’ MCNS– Based on
• Symptoms of Nephrotic Syndrome or relapse on weaning Prednisolone (Mean 24h Protein 2.5±3.5g/day)
• Biopsy confirming MCD• Mean Duration of Diagnosis 10±8 years
Pre-Rituximab
At baseline:– 9 in remission– 8 in partial remission– 8 full blown nephrotic syndrome– Mean dose steroid 26mg/day– 20 taking Ciclosporin (Mean 110
mg/day)
• Rituximab given at 375mg/m2 to max 500mg/dose
• Dose given at 0 + 6 months
Measures @ 0,1,3,6,9,12 months – Urinary Protein / Albumin / Cholesterol– Number of Patients in Complete Remission– Evidence of B Cell depletion– Cytokine Levels– Mean Number + Dosage of Patients on Steroid +
CycA
Results
Results
At 6 months (Dose 1 rituximab)9 off steroidsMean steroid dose - 8mg/dayMean Urine Protein – 0.4±0.02 g / 24h
At 12 months (Post 2 doses Rituximab)21 off steroidsMean steroid dose – 1.1mg/dayMean Urine Protein – 0.5±2.2g / 24h
Some Observations
• Not all of the patients that developed B cell repletion by 6 months relapsed– But relapses were associated with B Cell
repletion– ?B Cell independent effect of Rituximab
• Exclusively Japanese Cohort– ?Generalizability to Caucasian Cohort
Back to the Patient
Oral Cyclophosphamide
IV Cyclophosphamide
Rituximab 500mg
Currently
• Down to 7.5mg Prednisolone Daily• Albumin 48 g/L• No oedema• Creatinine 97 µmol/L
What would have happened if the patient
hadn’t responded???
Paper 2
NEJM November 2013
Outline of Study
“From Bench to Bedside”
– In Vitro Studies followed by testing hypothesis on 5 challenging nephrotic syndrome cases
BackgroundProtein B7-1 (aka. CD80)•Commonly found on antigen presenting cells
– Co-stimulatory signal for T-cells depending on ligand it binds to• CD28 – stimulatory / CTLA-4 - regulatory
•Not expressed by normal podocytes– But podocyte expression of B7-1
induced in models of proteinuria
Abatacept
• Fusion Protein– Fc region of the immunoglobulin IgG1– Extracellular domain of CTLA-4
• Blocks CD80 signalling through competitive binding for T-Cell ligands– Proven efficacy + safety for patients
with rheumatoid arthritis
Hypothesis
• Could blockade of B7-1 on podocytes with Abatacept ultimately mitigate proteinuria?
Methods – In Vitro Studies
1. Did intact B7-1 influence podocyte structure/function?
2. If so, did it interact with other ligands relevant to podocyte structure/function?
3. Could Abatacept modify the effects of intact B7-1 on podocyte structure/function?
Results – In Vitro Studies
1. Did intact B7-1 influence podocyte structure/function?
YES– Increased podocyte migration +
proteinuria associated with intact B7-1 expression
– No podocyte migration in cells expressing truncated B7-1 protein
Results – In Vitro Studies
2. If so, did it interact with other ligands relevant to podocyte structure/function?
YES– B7-1 found to bind to β1 integrin – β1 integrin essential ligand to bind
podocyte to GBM (via the protein Talin) and can modify actin cytoskeleton
Results – In Vitro Studies
3. Could Abatacept modify the effects of intact B7-1 on podocyte structure/function?
YES– Abatacept prevented B7-1 induced
podocyte migration and prevented B7-1/β1 integrin association
Translation to Practice
• Stained native renal biopsies from a catalogue of pathologies
• B7-1 Stained Strongly in:– Membranous Nephropathy
• (Regardless of PLA2R status)
– Primary FSGS– Minimal Change Disease
Application
5 patients with Primary FSGS refractory to ‘conventional’ therapies:
– 4 recurrent FSGS in Donor Kidneys– 1 Native Kidney FSGS
• Glucocorticoid Dependent with multiple relapses
•All 4 transplants had not responded to rituximab
• All 5 patients received Abatacept @ 10mg/kg SC– All transplants received 1 or 2 doses– Native FSGS receiving monthly
Abatacept injections
• All have had sustained remission of proteinuria even up to 48 months in 1 patient
The Future?
Funding•Cost of Rituximab (500mg vial)
– £873 per vial
•Cost of Abatacept (250mg vial)– £252 per vial
Remember vast majority still responding to conventional therapies
However…
• Will nephrology follow the oft-trodden path of the rheumatologist and turn things ‘on their head’?
• Long (>10yr) term outcomes not known!– Infections– Malignancies
Summary
• Biological Therapies present a promising treatment option for patients with challenging nephrotic sydromes
• Both ‘Targeted’ and ‘Off target’ therapies likely to have increased prominence for pharmaceutical research
• ‘Fast-tracking’ biologicals for additional uses tempting, but cost and long term follow-up data 2 issues impeding progress.