The role of filtered IgA in the progression of IgA nephropathy

Lead Research Organisation: University of Leicester
Department Name: Infection Immunity and Inflammation

Abstract

IgA nephropathy is a common form of kidney disease worldwide, and is characterised by deposits of a protein, Immunoglobulin A (IgA), on the sieving apparatus of the kidney. Around 30% of patients progress to kidney failure necessitating dialysis or transplantation, which themselves are associated with far greater rates of death compared to the general population. There are currently no specific treatments to slow or stop this progression.

A characteristic feature of IgA nephropathy, in common with many other forms of kidney disease, is the abnormal appearance of protein in the urine due to damage to the sieving apparatus. It has been established that the presence of protein in the urine is not only a marker of kidney disease but is also a cause of progressive kidney scarring, which eventually leads to kidney failure.

The precise type of protein responsible for damaging the kidney is unclear. Our preliminary experiments show for the first time that the IgA molecule itself is able to exert powerful effects on tubular cells which line the early part of the drainage system of the kidney, causing the release of chemical messengers known to drive the process of inflammation and scarring. I propose that IgA escapes from the blood into the urine through the damaged sieving apparatus in IgA nephropathy, subsequently causing these harmful effects.

I plan to investigate the interaction between IgA and tubular cells to determine how this might cause kidney scarring. By understanding this interaction we hope to use new targeted treatments to disrupt this process. Ultimately we hope that this will slow or even stop the process of scarring in patients with this condition.

I will be uniquely placed at Leicester to be able to utilise a bank of over 200 catalogued blood, urine and kidney biopsy samples from patients with IgA nephropathy which have been collected for over 20 years. I will analyse these samples to work out why some patients with this condition develop kidney scarring while others do not. I hope to identify factors that make certain patients more susceptible to progressive kidney disease in IgA nephropathy, so we can use these to more accurately predict outcome at time of diagnosis and identify new targets for drug development in the hope that this may ultimately enable clinicians to effectively treat this common kidney disease.

Technical Summary

IgA nephropathy (IgAN) is the commonest primary glomerular disease, and a leading cause of end stage renal failure worldwide. The strongest predictor of progressive kidney disease in IgAN is the development of tubulointerstitial inflammation and fibrosis. The development of non-selective proteinuria, occurring when high molecular weight proteins including immunoglobulins escape through the damaged glomerular filtration barrier, is thought to be a fundamental trigger for fibrosis, stimulating release of pro-inflammatory and pro-fibrotic mediators by proximal tubular epithelial cells (PTEC) into the renal interstitium. The presence of immunoglobulins in the urine has traditionally only been used as a marker of severity of glomerular injury, with little work done on their direct pathogenicity. My preliminary data shows that IgA is able to exert a potent effect on PTEC, favouring development of a pro-inflammatory and pro-fibrotic tubulointerstitial microenvironment in non-selective proteinuria.

I will test the hypothesis that "A major factor determining the development of progressive renal failure in IgAN is the presence in the serum of IgA1 with PTEC-specific pro-inflammatory and pro-fibrotic activity. As non-selective proteinuria develops this IgA1 enters the urine and augments PTEC activation, accelerating renal scarring".

My aims are to:
1. Detail key biochemical pathways activated by IgA1 in PTEC.
2. Characterise key receptors activated by IgA in PTEC, focussing on the role of the multi-ligand scavenger receptor megalin.
3. Study the role of candidate scavenger receptors in an in vivo model of IgAN.
4. Translate the above findings to human disease, utilising our bank of serum, urine and biopsy samples to perform in vitro and immunohistochemical studies.

These studies will provide new insights into the mechanisms by which filtered IgA may play a role in driving tubulointerstitial fibrosis in IgAN, and thus potentially reveal novel therapeutic targets

Planned Impact

IgA nephropathy is the commonest glomerular disease worldwide, and a leading cause of end stage renal failure. Peak incidence is in the 2nd and 3rd decade of life, therefore this is a disease that affects young adults. There is currently no disease-specific treatment, with management limited to anti-hypertensive therapies, in common with other chronic kidney diseases. Around 30% of patients progress to end stage renal failure necessitating treatments including dialysis. The replacement of renal function by dialysis is itself imperfect and socioeconomically costly. There remains a need to expand dialysis capacity in the UK, with the number of patients requiring dialysis increasing on an annual basis. The basic cost per person on dialysis per year is between £15 000 and £35 000, and the total cost of dialysis provision has been estimated to account for 1.5% of the overall NHS budget. Those affected by end stage renal failure are at far greater risk of mortality compared to the general population, with survival being 79% at one year from the first dialysis treatment. The personal cost to those individuals affected by chronic kidney disease and their families is significant. Therefore a major aim in clinical nephrology is to target progressive kidney disease before the occurrence of end stage renal failure.

There is now considerable evidence that the major factor driving progressive IgA nephropathy is tubulointerstitiial inflammation leading to irreversible scarring of the kidney. Through this Fellowship, I aim to understand the interaction between filtered IgA, proximal tubular cell activation, and kidney scarring. Through this I will seek to identify novel targets open to therapeutic manipulation in IgAN, to benefit this patient group.

Establishing an in vivo model of IgA nephropathy at the University of Leicester will allow us to test therapeutic agents in a pre-clinical setting beyond this Fellowship. We have extensive experience with both pre-clinical and clinil trials in our research group, which benefits from being led by both academic clinical nephrologists and non-clinical scientists. We have established collaborations with the pharmaceutical industry, who fund aspects of our research programme, and other national and international research groups. We are linked to the NIHR-Collaborations for Leadership in Applied Health Research and Care (CLAHRC) for Leicestershire, Northamptonshire and Rutland, and the NIHR Biomedical Research Unit in Cardiovascular Disease in order to achieve these translational goals.

I will utilise an extensive bank of clinical samples collected from patients with IgA nephropathy. Through my Fellowship, and in longer-term work, we aim to identify factors that can aid us more accurately predict rates of disease progression and prognosis in IgA nephropathy before renal scarring occurs. During this Fellowship, I will ascertain whether the structure of an individual's IgA molecule or their proximal tubular epithelial cell (PTEC) receptor expression profile correlate with disease progression. This Fellowship has therefore been designed to have a direct impact, beyond the academic environment, on renal patient care.

Publications

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Boyd Jk, Cheung Ck, Barratt J (2014) Encyclopedia of medical immunology

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Cheung C (2012) Evaluation and management of IgA nephropathy in Clinical Medicine

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Cheung C (2014) IgA nephropathy. in British journal of hospital medicine (London, England : 2005)

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Cheung Ck IgA, and not IgG, is a potent trigger of proximal tubular cell activation in IgA nephropathy in 13th International Symposium on IgA nephropathy (WCN Satellite Symposum)

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Cheung Ck, Boyd Jk, Barratt J (2014) Practical Nephrology

 
Description Doctoral Training Supplement
Amount £2,500 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 11/2014 
End 11/2015
 
Description Intercalated BSc
Amount £5,000 (GBP)
Organisation Kidney Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2013 
End 09/2014
 
Description Intercalated BSc award
Amount £4,000 (GBP)
Organisation International Association of Pathologists (IAP) 
Sector Charity/Non Profit
Country United States
Start 09/2013 
End 09/2014
 
Description Research project grant
Amount £194,049 (GBP)
Funding ID RP61/2014 
Organisation Kidney Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 12/2014 
End 12/2017
 
Description Travel Grant
Amount $1,000 (USD)
Organisation National Institutes of Health (NIH) 
Sector Public
Country United States
Start 05/2013 
End 11/2014
 
Description Walls Bursary
Amount £1,000 (GBP)
Organisation Renal Association 
Sector Charity/Non Profit
Country United Kingdom
Start 11/2013 
End 11/2014
 
Description Dr Frederick Tam 
Organisation Imperial College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Patient samples for analysis Methodology for purification of IgA
Collaborator Contribution Expertise on in vivo models of IgA nephropathy
Impact Publication: Spleen tyrosine kinase is important in the production of proinflammatory cytokines and cell proliferation in human mesangial cells following stimulation with IgA1 isolated from IgA nephropathy patients. Kim MJ, McDaid JP, McAdoo SP, Barratt J, Molyneux K, Masuda ES, Pusey CD, Tam FW. J Immunol. 2012 Oct 1;189(7):3751-8. Ongoing collaboration in a clinical trial in IgA nephropathy using the spleen tyrosine kinase inhibitor, fostamatinib, for which Leicester is a recruiting centre
Start Year 2013
 
Description Professor Bruce Molitoris, Indiana University 
Organisation Indiana University
Department Indiana Center for Biological Microscopy
Country United States 
Sector Academic/University 
PI Contribution We are in the process of purifying IgA for study on an intravital model, to study renal handling of IgA
Collaborator Contribution Training on intravital microscopy
Impact UK Renal association Walls bursary awarded for further visit to conduct experiments
Start Year 2013
 
Description Professor H. Terence Cook 
Organisation Imperial College London
Department Division of Immunology and Inflammation
Country United Kingdom 
Sector Academic/University 
PI Contribution Development of a mouse model of IgA nephropathy
Collaborator Contribution Expertise in mouse models, analysis of data and transgenic models
Impact Research ongoing
Start Year 2013
 
Description 1st UK IgA nephropathy patient information day 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Participants in your research and patient groups
Results and Impact Approximately 200 patients and their families attended this patient information day, for which I was a member of the organising committee. The day involved a mixture of lectures by experts in the area from our research group and others, and patient led discussions. The day was an opportunity to inform patients of ongoing laboratory and clinical based research and trials.

A patients support group was formed which is advising on an ongoing clinical trial
Year(s) Of Engagement Activity 2014
URL http://www.kidneyresearchuk.org/news/the-first-uk-iga-nephropathy-patient-information-day
 
Description Evening talk about IgA nephropathy 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Postgraduate students
Results and Impact Approximately 50 postgraduate students and patients attended an evening event themed for Rare diseases day. I was invited to speak at this event by the charity Kidney Research UK, and gave an update about current research in IgA nephropathy, The event helped to raise awareness about kidney disease, current research and also raised funds for charity.
Year(s) Of Engagement Activity 2016
URL http://pubhdleicester.wix.com/pubhd#!about1/c4xz
 
Description IgA nephropathy patient group laboratory visit 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Patients, carers and/or patient groups
Results and Impact 7 patients with IgA nephropathy and 2 representatives from Kidney Research UK attended for a visit to the laboratory, to observe current research taking place in the disease. We also organised a series of interactive talks, which generated discussion following this and interest in further developing a patient support group, and more days to increase interaction between clinicians, researchers and patients.
Year(s) Of Engagement Activity 2015