Sensing a real breakthrough in fighting kidney disease

After just one year, Professor Andrew Rees and his team on the MACRORIEN project in Vienna have produced such novel results that the whole focus of the research has dramatically shifted on to what was once considered a rather ordinary protein - LAMP-2 - and the implications could be significant.

Professor Andrew Rees has been working with kidney disease for more than 30 years, a timescale which has seen dramatic changes in understanding. In the past perceptions of kidney disease were all about dialysis machines and kidney transplants that are used to treat kidney failure, which was considered a rare event. Over the last 10 years it has become clear that chronic kidney disease is in fact common and affects eight to 10 per cent of the population often without them being aware of it. The key questions now are how to detect kidney disease in people without symptoms, how to identify the individuals whose kidney disease will progress to kidney failure and how to prevent that happening.

Rees’s work concentrates on glomerulo-nephritis, a group of inflammatory kidney diseases that often cause kidney failure. The outlook for patients with glomerulonephritis has improved greatly and Rees himself has played a significant role in this positive development, at both clinical and research levels, with his work in one of the most aggressive types of glomerulonephritis - focal necrotizing glomerulonephritis (FNGN). His clinical studies on the removal of the auto-antibodies in this disease has led to the formulation of successful treatments.

Rees’s work with the MACRORIEN project (Renal Macrophages as Natural biosensors and therapeutic targets), a collaboration with Dr Renate Kain and Professor Dontscho Kerjaschki to study the role of autoimmunity in pauci-immune FNGN - the most common type of FNGN - identified a potential pathogenic role of auto-antibodies to lysosomal membrane protein-2 (LAMP-2) and showed how these auto-antibodies can be induced by exposure to a common bacterial protein through a process known as molecular mimicry. The breakthrough results are prompting a re-evaluation of liver disease pathogenesis.

The premise of the research was to identify specific, underlying causes of the disease in order to develop effective, precise treatments. In gaining a clearer understanding of the role of auto-antibodies, Professor Rees is confident that improved treatments can now be developed. Additionally, his work with the Marie Curie Excellence Chair Programme, which concluded at the end of FP6, allowed him to re-focus his work on valuable research, with the benefit of the programme allowing him to move around Europe working with research teams in many universities.

“My research interest has been the mechanisms of injury in a group of kidney diseases called glomerulo-nephritis,” he explains. “These are diseases in which the body’s immune system attacks the kidney rather than defends the person against infection or cancers. My particular interest has been the most aggressive of the various types of glomerulonephritis – focal nequitising glomerulonephritis (FNGN).

In the laboratory, we try to understand the basic mechanisms responsible for that, while the clinical work has been designed to devise better treatments for them.”

This has been a successful time for clinical scientists in this field. Over the past 20 years, the ability to treat this type of glomerulonephritis has improved dramatically – at least 80 per cent of the people with FNGN used to develop kidney failure very rapidly, while these days the figures are reversed and at least 80 per cent continue with functioning kidneys. Unfortunately, the use of steroids and immuno-supressive drugs in the treatment of FNGN has come with greater risks of infection and severe side effects. This spurred Professor Rees towards finding better, targeted treatments and the Marie Curie Chair proved to be the perfect vehicle.

Professor Rees then moved to The Institute of Clinical Pathology at the Medical University in Vienna, headed by Professor Dontscho Kerjaschki, one of the best kidney research centres in the world. Here, Professor Rees proposed to investigate macrophage cells; white blood cells that circulate around the body looking for tissue damage before returning to the bloodstream once more. What interested Professor Rees was that this macrophage function is extremely plastic, meaning that if they encounter one type of injury they become activated in a particular way, developing a specific set of properties that, in an evolutionary sense, would best deal with the situation they encounter – and if they encounter a different situation, then they develop a different set of properties to deal with that situation. This means that macrophages can be activated either to cause damage or to repair it depending on the circumstances. Professor Rees hypothesises that macrophages could potentially be manipulated to perform therapeutic functions. It seems a possibility, as cancer cells manipulate macrophages to fuel tumour growth. Professor Rees also intended to look at how an underlying abnormality in the immune system causes macrophages to attack healthy tissue.

However, his research has now changed direction to focus on the reason why such abnormalities exist in the immune system to begin with, discovering that abnormal antibodies (auto-antibodies) bind to molecules in the kidney glomerulus in FNGN and recruit macrophages to attack the kidney. “The work builds on the observation that some patients with FNGN have auto-antibodies that recognise a protein called lysosomal membrane associated protein 2 (LAMP-2),” explains Professor Rees. “This discovery was made some years ago by Dr Kain and Professor Kerjaschki in a small number of patients and was interesting because LAMP-2 is expressed on the surface of white blood cells and the endothelial cells that line the capillaries in the gomerulus that are the target of injury in FNGN.”

“Our new work shows that over 90 per cent of our group of patients had these antibodies for LAMP-2, while the presence of these antibodies correlated with active disease. We then discovered that if you injected antibodies that were specific to LAMP-2 into rats, they developed a disease that was indistinguishable from the human disease. Finally, if you took cultured human endothelial cells, the lining cells of the blood capillaries, and grew them in tissue culture plates and incubated them with the antibodies, then these antibodies activated the cells and also killed some of the cells.”

Additionally, the research team found that the antibodies reacted with region in the LAMP-2 molecule identical to FimH, a bacterial protein found on bacteria known to cause common human infections. “That raised the question whether synthesis of the auto-antibodies might be initiated by abnormal response to infection with a bacterium bearing FimH.” The team tested on rats, observing that anti-LAMP-2 auto-antibodies also bound to FimH, rats immunised with FimH developed anti-FimH antibodies that also recognised LAMP-2, and immunised rats also developed the disease identical to the human FNGN. Professor Rees concludes that FNGN might start from molecular mimicry, where antibodies attack healthy cells that resemble invading cells.

Professor Rees believes that “the implications are potentially huge.” If auto-antibodies do cause FGNG then measuring the level of antibodies in a person’s system would allow for individual, targeted treatment, as well as being able to predict relapses. Further study of the abnormal immune response would hopefully allow the disease to be treated more effectively or, even, cured. “That is a difficult and long-term aim,” says Rees. “But, in theory, at least, it is a possibility.”

For more information contact Professor Andy Rees at andrew.rees@meduniwien.ac.at

Published: Thursday, 12th November 2009

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