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Science Omega Review UK: issue 2 www.scienceomega.com
T
he Medway School of Pharmacy is a
joint venture between the Universi-
ties of Kent and Greenwich, and is
located at the heart of a new multi-univer-
sity campus development at Chatham
Maritime in Medway, Kent. Founded in
2004, the school is relatively new, but since
its inception, and latterly under the guid-
ance of Director of Research Professor
Alistair Mathie, a research environment has
actively been developed and maintained.
Mathie, in line with the emergent research
strategies of both research councils and
industry, has instilled the ethos that where
possible, research should be driven by a
realistic bench to bedside theme, or
industrial collaboration. Both considera-
tions encourage translational activity.
The school has three main research
groupings: Chemistry and Drug Discovery,
Clinical and Professional Practice, and
Biological Sciences. Within the Biological
Sciences grouping is the Urinary Systems
Physiology Unit, founded in 2011 and jointly
headed by Drs Claire Peppiatt-Wildman
and Scott Wildman. The primary aim of the
unit is to address prominent and costly
problems of urinary/renal system disease
as identified by local healthcare providers.
The units team (Fig. 1) strives to produce
high-quality and internationally recognised
research through links, facilitated by Helen
Leech, a dedicated member of the univer-
sitys Research Services team, along with
healthcare providers and industry.
Innovative research within
the unit
Biomedical research within the unit
focuses on three main areas: regulation of
renal medullary blood flow in health and
disease, local regulation of renal tubular
transport mechanisms, and urinary bladder
cell signalling and the causative mecha-
nisms of urinary incontinence. Novel
methodologies that are either unique to
the unit or to the UK are utilised in all three
areas to underpin research goals.
Regulation of renal medullary blood
flow in health and disease
The unit pioneers real-time imaging of both
live ex vivo kidney slices and in vivo iso-
lated perfused kidneys. These approaches,
both previously validated,
1, 2
are used to
increase the understanding of poorly
defined basic physiological processes in the
kidney, delineate mechanisms underlying
kidney dysfunction (whether in the context
of renal disease or drug-induced toxicity),
and currently, provide industrial partners
with experimental screening models.
For example, the live ex vivo slice model
has recently been used to define a locus of
blood flow control in the kidney. Investiga-
tions have revealed that contractile pericyte
cells regulate blood flow through vasa recta
capillaries. Follow-up investigations have
demonstrated a number of new crosstalk
pathways that link regulation of blood flow
with tubular epithelial cell demands, which
are essential in ensuring the continued
production of appropriately concentrated
urine and in protecting the tissue against
ischemia and ensuing kidney failure.
2, 3
Avant-garde urinary system research in Kent
Embracing translation
A
C
B
D
Fig. 1: A: Top left: the Urinary System Physiology Unit, Medway School of Pharmacy (from left to right,
Stephen Kelley, Kadeshia Dunn, Scott Wildman, Carol Crawford, Claire Peppiatt-Wildman, Rebecca Birch,
Mark Kelly). B: Jonathan Duckett, Medway NHS Foundation Trust. C: Kent Kidney Care Centre, East Kent
Hospitals University NHS Foundation Trust (third from left, Paul Stevens). D: Helen Leech, Research
Services, University of Kent
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www.scienceomega.com Science Omega Review UK: issue 2
Furthermore, a recent application of this
approach has been to delineate mechanisms
of immunosuppressant drug-induced toxi-
city, with a view to improving renal function
in renal transplant patients who receive
immunosuppressant therapy to prevent
organ rejection. The unit has demonstrated
that a specific class of commonly used
immunosuppressant drugs, calcineurin
inhibitors (CNIs), induce vasoconstriction
of renal capillaries via pericyte cells, to
exacerbate renal medulla ischemia, which
ultimately contributes to nephrotoxicity
(Fig. 2). Investigations are under way to
determine if this adverse side-effect can be
minimised pharmacologically.
Local regulation of renal tubular
transport mechanisms
In addition to, and often in combination
with, imaging-based approaches, the unit
employs patch clamp electrophysiology
techniques to record ion flux in cells of
microdissected split-open renal tubules.
This provides information on ion transport
mechanisms in the various nephron seg-
ments
4
and increases the understanding
of poorly defined basic physiological
processes and mechanisms underlying
kidney dysfunction.
The movement of ions (and water) across
cells of the nephron is complex, varies
along the various segments, and requires
local and rapid regulation. Dysregulation
is likely responsible for many idiopathic
disorders of a renal origin, including
essential hypertension. Under the expert
tuition of Professor Pascal Houillier (Paris
Descartes University, France), the unit has
recently acquired a new experimental
approach to address renal tubular trans-
port research questions intact isolated
perfused renal tubule technique and
now acquires data from combined ion
flux measurements, imaging and analysis
of collected perfusate. Both experimental
approaches, i.e. recording from microdis-
sected split-open renal tubules and intact
isolated perfused renal tubules, are unique
in the UK and only available in a handful
of laboratories worldwide.
Urinary bladder cell signalling and
urinary incontinence
As the units name implies, research inter-
ests encompass both kidney and bladder
function. A significant proportion of the
efforts are dedicated to delineating the
causative mechanisms of urinary inconti-
nence. This is a highly prevalent and dis-
tressing condition, which has a significant
impact on health related quality of life in
millions of individuals worldwide, particu-
larly the elderly. Urinary incontinence is
also associated with a substantial financial
burden, costing the NHS a minimum of
350m per year. Current research suggests
that urinary infection might contribute
substantially to the presentation of
patients with symptoms associated with
urinary incontinence.
5
Current research in
the unit, building on previous collabora-
tions with Professor James Malone-Lee
(Department of Medicine, University
College London), has identified a novel
approach to identify a chronic low-level
bacterial infection in the cells lining the
bladder and an associated production of
excreted biomarkers,
6
which are believed
to be central to the aetiology of urinary
frequency and urgency, and the early
detection of urinary infection, which if left
untreated results in the chronic condition
of urinary incontinence.
Translational research within
the unit from the clinicians
perspective
To ensure high-quality and prominent
translational research, the unit has forged
links with local healthcare service teams
at Kent Kidney Care Centre (East Kent
Hospitals University NHS Foundation Trust)
and Obstetrics and Gynaecology (Medway
NHS Foundation Trust).
Dr Paul Stevens (Consultant Nephrologist
and Associate Medical Director, Kent
Kidney Care Centre) acknowledges that at
first glance, making research a high prior-
ity in an organisation providing healthcare
may seem profligate, at a time when the
Fig. 2: Real-time imaging of live ex vivo kidney slices to study the effect of cyclosporine A (CsA) on renal vasa
recta capillary diameter. (A) Differential interference contrast (DIC) imaging of pericyte-mediated constriction
of in situ vasa recta capillaries by CsA (3m). Images of vasa recta taken from a time series experiment in which
live kidney slices were exposed to CsA. (Ai) shows a typical field of view of vasa recta under control conditions,
the pericyte is highlighted (white/dashed oval). (Aii) shows vasa recta constrict at pericyte sites (red dashed
lines) during exposure to CsA. (Aiii) shows vasa recta diameter returns toward original diameter when CsA is
removed. Vessel diameter was measured every 5s throughout the experiment at a pericyte site (red dashed
lines) and a corresponding non-pericyte site (yellow dashed lines). (B) A representative trace from CsA (3m)
superfusion, showing change in vessel diameter over time at a pericyte site (black line) and corresponding non-
pericyte site (grey line). B is mean data showing the percentage change in vessel diameter at pericyte (black
bar) and non-pericyte sites (grey bar). (C) Cyclosporine (3m) caused a significantly greater constriction at peri-
cyte sites compared to non-pericyte sites (mean SEM, *P<0.05; n=8)
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Science Omega Review UK: issue 2 www.scienceomega.com
NHS is under pressure to make stringent
cost-efficiency savings. However, it is sig-
nificant that healthcare institutions actively
involved in clinical and epidemiological
research deliver better healthcare with
improved outcomes when compared with
those who do not.
7
Professor Jonathan
Duckett (Consultant Gynaecological
Surgeon and Head of Research and Devel-
opment, Obstetrics and Gynaecology,
Medway NHS Foundation Trust) provides
the viewpoint that clinicians are able to
study the effects of different interventions
upon their patients, but until the causative
mechanisms are truly understood, inter-
ventions will be generic and poorly
focused on the correct disease pathology.
In simple terms, the units current research
collaborations follow a simple model: the
epidemiological research by clinicians
generates knowledge concerning burdens
of disease, and defines potential outcomes
of interest to researchers. Observational
studies generate hypotheses to be tested
through clinical research and laboratory
research, mechanisms of disease eluci-
dated, and models of intervention tested
prior to development of therapeutic tools.
This model serves to bridge two important
gaps: the translational gap between labo-
ratory research and clinical research, and
the gap between clinical research and
improved outcomes. Importantly, this is not
a single loop process, and development of
therapeutics through laboratory research,
translation into clinical trials and imple-
mentation into clinical practice generate
new questions that can only be answered
by returning to laboratory research.
Future of the unit and urinary
system research in the UK
The future of the Urinary System Physiology
Unit looks bright. Original methodologies to
address prominent healthcare concerns, in
collaboration with local healthcare services,
are resulting in internationally recognised
research. However, the ultimate success of the
unit is dependent on sustained funding. This
is a significant challenge when competing with
researchers working in more heavily endorsed
research fields such as cancer, neuroscience
and cardiovascular disease. Currently, the unit
is predominantly funded by pharmaceutical
companies based overseas, and to a lesser
extent the UK Research Councils, which is
ponderous. In a recent Public Service Review,
Professor Philip Kalra, Chair of the National
Institute for Health Research Comprehensive
Clinical Research Network (NIHR CCRN) Renal
Specialty Group, highlighted that UK science
is responsible for recent and hugely impor-
tant discoveries that underpin renal disease.
8
Unfortunately, this is not reflected in the
number of research grants awarded for UK
urinary system related research. According
to the mainly post-2006 avaiable data from
European PubMed Central, the 'big four'
(The Wellcome Trust, NIHR, MRC and BBSRC)
collectively fund / have funded < 400
research grants with a urinary system focus
(key words: 'renal', 'kidney', 'bladder', or
'urinary'), equating to < 1.6% of grants
funded. In monetary terms, using the RCUK
Gateway to Research, there are 50 active
MRC and BBSRC funded research grants (all
types; key word - 'renal'), totalling 5m. The
main Association of Medical Research Chari-
ties (AMRC) funding renal research is Kidney
Research UK (KRUK), with its budget
totalling 3.5m per year. In stark contrast,
the USAs National Institutes of Health pre-
dicts its spending on research into kidney
and urological disease in 2013 alone to be
$558m and $543m, respectively. The ques-
tion is, can the UK maintain its renal medi-
cine/research legacy indefinitely, and what
will this mean for the huge social and eco-
nomic burden of urinary system disease?
More information on the Urinary System
Physiology Unit can be found at:
www.msp.ac.uk/research/biosciences-
team/urinary-system-group/index.html
Acknowledgements
We thank Pauline Pinkos, of the National Kidney Federation
and Heather Harper of KRUK, for advice on current funding.
1
Hall A M et al (2011), Multiphoton imaging of the
functioning kidney. J Am Soc Nephrol 22(7):1297-1304
2
Crawford C et al (2012), An intact kidney slice model to
investigate vasa recta properties and functions in situ,
Nephron Physiol 120(3):17-31
3
Crawford C et al (2011), Extracellular nucleotides affect
pericyte-mediated regulation of rat in situ vasa recta
diameter, Acta Physiol 202(3):241-251
4
Wildman S S et al (2008), Sodium-dependent regulation of
renal amiloride-sensitive currents by apical P2 receptors
5
Harber M et al (2012), Asymptomatic bacteriuria and
urinary tract infection in renal transplantation, Brit J
Renal Med 17(1):4-7
6
Contreras-Sanz A et al (2012), Simultaneous quantification
of 12 different nucleotides released from renal epithelium
and in human urine samples using ion-pair reversed-phase
HPLC, Purinergic Signal 8(4):741-751
7
Roger V L (2011), Outcomes Research and Epidemiology
- The Synergy Between Public Health and Clinical Practice,
Circ Cardiovasc Qual Outcomes 4:257-259.
8
Kalra PA (2012), A kidney research revolution, Public Service
Review: UK Science and Technology 9th October. 2012.
Co-authors
Dr Scott S Wildman, Joint Head of Urinary System Physiology
Unit; Mark Kelly, PhD student in Urinary System Physiology
Unit; Helen Leech, Research Services, University of Kent;
Jonathan Duckett, Consultant Gynaecological Surgeon
and Head of Research and Development at Medway NHS
Foundation Trust; Paul Stevens, Consultant Nephrologist &
Associate Medical Director at Kent Kidney Care Centre.
Dr Claire M Peppiatt-Wildman
Urinary System Physiology Unit
Medway School of Pharmacy
Tel: +44 (0)1634 888828
c.m.peppiatt@kent.ac.uk
www.msp.ac.uk