Journal Club - Biologics for Proteinuric Kidney Disease

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An early taste of a Journal Club meeting on the use of Rituximab and Ababtacept in Nephrotic Syndrome

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  • They are believed
    to serve at least four distinct functions: Regulation of
    glomerular permselectivity (10); structural support for the glomerular
    capillary, cooperating with mesangial cells to resist the
    distensive force of intracapillary hydraulic pressure (11); remodeling
    the glomerular basement membrane (GBM), in cooperation
    with endothelial and mesangial cells (12); and endocytosis
    of filtered proteins (13).
  • Journal Club - Biologics for Proteinuric Kidney Disease

    1. 1. Biologics in Proteinuric Kidney Disease Journal Club Dec 2013
    2. 2. What will I cover? • 2 Papers – Nephrotic Syndrome – Biological therapies where ‘conventional’ treatment has failed • Implications for Future Treatment Strategies / Funding etc.
    3. 3. Glomerular structure facilitating ultrafiltration
    4. 4. The Glomerular Filtration Barrier
    5. 5. 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
    6. 6. Ronco P. JCI. 2007 117(8):2079-82.
    7. 7. Failure of the Filtration Barrier in Nephrotic Syndrome
    8. 8. Case from Practice 55 year old man Presented 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
    9. 9. 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)
    10. 10. • 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
    11. 11. Paper 1
    12. 12. 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
    13. 13. 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 signalling Fornoni et al 2011 
    14. 14. 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
    15. 15. 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)
    16. 16. • 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
    17. 17. Results
    18. 18. Results At 6 months (Dose 1 rituximab) 9 off steroids Mean steroid dose - 8mg/day Mean Urine Protein – 0.4±0.02 g / 24h At 12 months (Post 2 doses Rituximab) 21 off steroids Mean steroid dose – 1.1mg/day Mean Urine Protein – 0.5±2.2g / 24h
    19. 19. 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
    20. 20. Back to the Patient IV Cyclophosphamide Oral Cyclophosphamide Rituximab 500mg
    21. 21. Currently • • • • Down to 7.5mg Prednisolone Daily Albumin 48 g/L No oedema Creatinine 97 µmol/L
    22. 22. What would have happened if the patient hadn’t responded???
    23. 23. Paper 2 NEJM November 2013
    24. 24. Outline of Study “From Bench to Bedside” – In Vitro Studies followed by testing hypothesis on 5 challenging nephrotic syndrome cases
    25. 25. Background Protein 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
    26. 26. 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
    27. 27. Hypothesis • Could blockade of B7-1 on podocytes with Abatacept ultimately mitigate proteinuria?
    28. 28. 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?
    29. 29. 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
    30. 30. 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
    31. 31. 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
    32. 32. 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
    33. 33. 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
    34. 34. • 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
    35. 35. 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
    36. 36. 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
    37. 37. 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.

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