PROFILE
Renal medicine at UCL
T
he UCL Centre for Nephrology
Royal Free is situated at the
Royal Free Hospital and Royal
Free Campus of UCL Medical School
in north London. It became a large
single clinical service and academic
unit in 2006 when renal services at
the Middlesex, University College, and
Royal Free Hospitals merged. Our
centre comprises 25 consultant
nephrologists, six with primary UCL
academic appointments and 10 with
honorary UCL academic appointments,
plus five consultant transplant surgeons.
Academic nephrology and research in
the UK over the last 30-40 years have
been largely dominated by immunopathology with a focus on glomerular
disease (glomerulonephritis) and
kidney transplantation. Consequently,
many UK academic renal centres are
known for their specialist knowledge
and research in one or two key areas.
The UCL Centre for Nephrology Royal
Free is unique in having a wide
breadth of clinical and research
expertise (applied epithelial physiology
and pathophysiology, renal genetics
and cell biology, immunology and
inflammation, mineral metabolism,
cardiovascular disease, and modalities
of renal replacement therapy), which
is applied to its research, clinical care
and training. Our guiding ethos is that
all our staff are encouraged to engage
in collaborative research and exploit
the collective expertise.
The prevalence and incidence of
chronic kidney disease (CKD) is
increasing for many reasons – greater
public awareness, an ageing population, more advanced and complicated
surgery carried out in older patients,
and fewer deaths from infection, heart
attacks and some forms of cancer.
CKD is recognised to be a silent
epidemic with numbers expected to
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increase year on year.
Many patients will have a
routine blood test at their
GP’s surgery, usually
including measurement of
their blood creatinine level
to screen for reduced
kidney function; this
method is relatively insensitive and better methods
are needed to detect and
treat kidney disease earlier
and thereby reduce the
high costs of dialysis
treatment and kidney
transplantation, and lessen
impact on quality of life.
The following summary of
our key research themes
and activities demonstrates our comprehensive
clinical and basic research,
which forms the foundation for our
highly regarded clinical and research
training programmes.
CKD and cardiovascular disease
(CVD) risk: David Wheeler
Patients with CKD have decreased life
expectancy despite treatment with
dialysis and kidney transplantation.
Many patients with advanced CKD die
prematurely of CVD and reducing CVD
risk is essential for improved survival.
The association between CVD and
kidney function has been clearly
defined in epidemiological studies in
which we have participated, including
the CRIB and LACKABO cohort studies,
whilst SHARP, an interventional study
in which we took a leading role, has
confirmed the benefits of lipid-lowering
therapy. The mechanisms by which
reduced kidney function increases
CVD risk, particularly with respect to
non-atherosclerotic disease, are still
poorly understood. Our recent work has
focused on the abnormal calcification
of blood vessel that is common in
Public Service Review: UK Science & Technology: issue 4
The prevalence and incidence of
chronic kidney disease is increasing
for many reasons…
Members of the centre and delegates at a recent
Nephrology Day meeting
CKD. This may be worsened by our
current calcium and vitamin D-based
treatments aimed at controlling overactivity of the parathyroid glands (which
normally regulate mineral metabolism
and bone turnover). Our primary goal is
to understand the local and systemic
factors that affect mineral metabolism
and cause arterial calcification.
CKD and progressive fibrosis:
Jill Norman
Following kidney injury or disease,
damage can be repaired and organ
function restored. However, in some
cases the normal healing response
fails and scarring continues causing
CKD. Progressive scarring replaces
normal kidney tissue with non-functional fibrotic tissue and kidney
function is lost. Ultimately, this can
lead to kidney failure and the need
for dialysis or kidney transplantation.
Therapies that can retard or halt
progressive scarring are limited and
there is a need for novel therapeutic
PROFILE
Fig. 1: Destruction of the glomeruli in a
patient with vasculitis. One of the goals of our
research is to re-educate the immune system
to stop this injury and allow the kidney to heal
strategies. The key to this is understanding the basic mechanisms
underlying fibrosis. Our work focuses
on the biology of kidney fibroblasts,
since in CKD the number of fibroblasts increases and the cells become
activated to produce large amounts
of fibrous tissue. Gene profiling and
proteomic approaches are used to
identify differences in normal and
CKD-derived fibroblasts. Mechanistic
studies explore how altered gene
expression is regulated and how
changes alter fibroblast behaviour
and function, as well as fibroblast
interactions with other renal cell
types. We are also trying to identify
biomarkers in blood and urine
predictive of fibrosis and define key
molecular targets for therapy, as well
as test novel anti-fibrotic agents.
Lipids, the kidney and
vascular injury: Xiong Z Ruan
Dyslipidaemia is the most common
metabolic disorder at all stages of
CKD and contributes to vascular
injury in CKD patients. We have
shown that inflammation in CKD
increases cholesterol influx and
reduces lipid efflux from cells thus
diverting cholesterol from the blood
to the tissues. This cholesterol
redistribution causes cholesterol to
accumulate in the kidney and in the
arterial wall, and lowers circulating
cholesterol levels. This may be why
CVD risk is increased in CKD, yet
plasma cholesterol levels (usually
directly correlated with CVD risk) are
not high. Inflammatory stress, a
feature of CKD, also increases intra-
(A)
(B)
Fig. 2: (A) Microtubule cytoskeleton (green) of branching podocytes; (B) ureteric tree (green) and
glomeruli (red) of embryonic mouse kidney
cellular cholesterol synthesis, which
adds to lipid accumulation and foam
cell formation (a feature of atherosclerosis) in the kidney and blood
vessels. This suggests that the level
of circulating cholesterol is not solely
a reliable predictor of cardiovascular
and renal risks in patients with CKD.
We are working to identify new
biomarkers in blood or cells for risk
assessment and to define key
molecular targets that can block the
cholesterol redistribution in CKD.
Acute kidney inflammation:
Alan Salama, Mark Little,
John Connolly and Aine Burns
Around 1,000 people annually in the
UK develop vasculitis, an inflammation of small blood vessels. When it
affects the kidneys, this form of
glomerulonephritis is one of the
commonest causes of kidney failure
requiring dialysis or transplantation. It
is often sudden in onset and sometimes associated with bleeding from
the lung, frequently affecting those
who were otherwise well (Fig. 1). Our
research aims to find ways to control
this inflammation without disabling
the body’s immune system that
normally protects against infection
and cancer. Vasculitis is rare and the
diagnosis can be missed, so we are
trying to find better disease markers
for earlier detection and to monitor
its progress, and we have established
a UK registry of all affected patients.
We have found that the level of a
protein, the mannose receptor, influences kidney damage in this disease
and we are investigating patients with
high levels of mannose receptor in
their blood or urine to determine if
they develop more severe kidney or
lung injury.
Tissue oxygen sensing and
renal genetics: Patrick
Maxwell, Margaret Ashcroft
and Daniel Gale
Our main goal is to understand the
key cellular mechanisms involved in
oxygen-sensing and hypoxia signalling
in mammalian cells, in particular, the
role of the hypoxia-inducible factor
(HIF) family of transcription factors in
disease: anaemia, cardiovascular and
renal diseases, and cancer. A pivotal
discovery was that the von HippelLindau tumour suppressor protein is
crucial for oxygen sensing. We have
also discovered novel molecular
mechanisms that link mitochondria
with the oxygen-sensing machinery
and have identified new therapeutic
approaches to target the HIF pathway
in cancer. As part of our broad interest
in genetic factors in kidney disease,
we recently discovered a new genetic
kidney disease, CFHR5 nephropathy,
which is a common cause of kidney
disease in Greek Cypriots.
Renal genetics in paediatric
and adult nephrology: Robert
Kleta, Detlef Böckenhauer,
Riko Klootwijk, Horia Stanescu
and Anselm Zdebik
Genetics is revolutionising medicine.
Better and cheaper genetic technologies enable us to quickly understand
genetic components of kidney disease,
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PROFILE
culture, metanephric organ culture and
transgenic mouse technology to study
podocyte morphogenesis. Fig. 2 shows
the microtubule cytoskeleton of
branching podocytes in vitro alongside
the arborising ureteric tree and
podocytes in mouse embryonic
metanephric organ culture.
Polycystic kidney disease:
Pat Wilson
Fig. 3: In the image depicted, a live intact rat
kidney has been perfused with a fluorescent
cationic dye that is taken up into mitochondria
according to their membrane potential, which
is generated by respiratory chain activity and
drives ATP synthesis, providing energy for the
cells. The tubules are densely packed with
elongated mitochondria, which lie in a
basolateral distribution, close to the ion
pumps that power solute transport and are the
main consumers of ATP in the kidney
and to study individual families with
unknown kidney disorders, and unrelated individuals with apparently similar
kidney problems. Recent work from our
group, in collaboration with colleagues
throughout the UK and abroad,
includes: the elucidation of a rare,
but highly informative, kidney disorder
also affecting the brain (epilepsy and
incoordination) and hearing – EAST
syndrome; establishing the genetic
basis of premature arterial calcification
in adults; and clarification of the genetic
components contributing to idiopathic
membranous nephropathy, another
common form of glomerulonephritis.
Podocytes and glomerular
filtration: Jenny Papakrivopoulou
Podocytes are specialised epithelial
cells, which, together with the
glomerular basement membrane
(GBM) and an endothelial cell layer,
form the kidney filtration barrier. During
kidney development, they acquire a
highly branched morphology, essential
for their role in glomerular filtration.
Although the importance of podocyte
morphology in glomerular function is
well-recognised, the mechanisms and
signal transduction pathways regulating podocyte architecture remain
poorly understood. We use a variety of
techniques, including podocyte cell
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Autosomal Dominant Polycystic Kidney
Disease (ADPKD) is the commonest
genetic cause of CKD with around
60,000 patients affected in the UK.
The kidney cysts develop before birth
and slowly expand to compress and
damage kidney tissue over many
years. We are working to define the
underlying mechanisms of cyst formation, identify potential drug targets,
and identify specific biomarkers that
predict progression and can be used
to monitor responses to therapy. We
have identified the epidermal growth
factor receptor proteins ErbB1 and
ErbB2 as potential therapeutic targets,
since their inhibition restores a normal
phenotype to human ADPKD cells in
culture. The efficacy of small molecule
inhibitors of ErbB1 and/or ErbB2 is
currently being evaluated and optimised in a mouse model of ADPKD.
Together with Jill Norman, we have
targeted abnormal fibrosis in ADPKD
for further therapeutic research.
Mitochondrial function in the
kidney: Andrew Hall
Mitochondria are intracellular
organelles that have a number of
important roles in tubular cells in the
kidney, including the provision of ATP,
which is required to power solute
transport along the nephron.
Mitochondrial dysfunction has been
implicated as a key step in the development of various kidney diseases.
We have developed imaging-based
techniques, using confocal and multiphoton microscopy, that allow the
study of various aspects of mitochondrial function in intact rodent kidney
tissue in models of human kidney
diseases (Fig. 3). We also perform
clinical studies of patients with
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genetic or acquired mitochondrial
diseases, using techniques such as
urine proteomic screening, in order to
investigate the effects of abnormal
mitochondrial function on the kidney
in humans.
Glucose and phosphate
transport: Ted Debnam, Joanne
Marks and Robert Unwin
Glucose transport across renal and
intestinal cells contributes to body
glucose balance and is markedly
altered in diabetes mellitus (DM). We
aim to elucidate the mechanisms
leading to altered intestinal and renal
glucose transport in DM. DM accounts
for almost 30% of patients developing
advanced CKD, so defining the role of
altered glucose transport in DM and
the relationship to its major renal
complication is likely to be important.
The intestine and kidneys are also
involved in the regulation of body
phosphate balance, which has been
linked to premature CVD and vascular
calcification in CKD. Phosphate overload occurs in CKD. In the absence of
adequate excretion by the kidneys to
prevent this, absorption by the intestine becomes an important therapeutic
target. We are investigating the mechanisms of phosphate absorption by
the intestine and how they are regulated, particularly by a group of novel
hormones called phosphatonins; one
in particular, FGF-23, has also been
implicated in vascular calcification.
Robert Unwin PhD, FRCP, CBiol, FSB
Head of Centre, Professor of
Nephrology and Physiology
UCL Centre for Nephrology Royal Free
UCL Medical School
Royal Free campus
Rowland Hill Street
London NW3 2PF
Tel: +44 (0)20 7830 2930
robert.unwin@ucl.ac.uk
www.ucl.ac.uk/medicine/nephrology