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.