Professor David Kluth

Background

Renal disease has a significant health burden and is increasing in incidence. Macrophages are a key inflammatory cell that has the ability to not only cause inflammation but are also important in resolving disease. Our work aims to harness the beneficial properties of macrophages to ameliorate disease.

Research Overview

Macrophage cell therapy in renal disease

Macrophages (MØ) are critical in development and resolution of many forms of inflammation and injury. MØ function can be modified either by gene transfer (principally using adenovirus) or ex vivo stimulation with drugs. These modified macrophages localise to sites of injury and have beneficial effects. We have shown this in glomerulonephritis with MØ expressing IL-4 or IL-10 and with MØ in which the NF-κB pathway is inhibited. The work in acute glomerulonephritis is continuing focusing on later stages of disease and determining which modifications are most effective in reducing acute and chronic inflammation. We have more recently shown the effects of MØ in renal ischaemia-reperfusion injury (IRI). MØ expressing hemoxygenase-1 (HO-1) localise to the site of renal IRI following systemic injection and can protect renal function. Our work is continuing to dissect the protective mechanisms of HO-1 expressing MØ. This is currently looking at their effects on platelet microaggregates, endothelial cell survival and renal blood flow. Further work will also involve determining in rat model of IRI whether local renal artery injection is more effective in protecting from IRI. As MØ are of potential clinical utility we have started a project with Dr Leslie Forrester to derive HO-1 expressing macrophages from murine embryonic stem (ES) cells. These ES derived MØ will be used in murine IRI to assess if they can achieve protection from renal failure. This approach will then be used on inducible adult ES cells. This research is geared towards a translational project in acute kidney injury where we would administer modified MØ to patients to aid recovery of renal function. This work is complemented by studies on the role of macrophages in renal IRI where we use depletion strategies to determine the role of macrophages. This suggests that MØ have an important role but that cell death induced by MØ depletion may also be important.

Hemoxygenase-1 in renal IRI

HO-1 is an important cytoprotective molecule which may be of benefit in renal IRI. We are studying the effects of inducing HO-1 using a heme arginate. This has shown protective effects on renal function. Reduced levels of HO-1 may also be important in the increased risk of IRI seen in the elderly. We are using a model of IRI in old and young mice to address this. We also have recently started a clinical trial of heme arginate to reduce ischaemic injury in cadaveric renal transplants.

Endothelin-1 (ET-1) and podocyte function

Proteinuria occurs in kidney disease and is an important cause of cardiovascular disease. Damage to the podocyte is one of the main causes of proteinuria. ET-1 is a potent vasoconstrictor that may contribute to renal disease and its antagonism may be of clinical benefit. To further understand the role of ET-1 we are assessing the effect of ET-1 on podocyte function in vitro using a human podocyte cell line. ET-1 causes production of pro-inflammatory cytokines by podocytes and this effect is antagonised by blockade of ETA receptor. We are also performing studies in rat and murine models of glomerular injury to assess whether ET-1 antagonism reduces renal injury, inflammation and proteinuria and if so by what mechanism this is achieved.

Other Responsibilities

Consultant nephrologist, Head of the Edinburgh Lupus and Vasculitis service, member of the kidney live transplantation related multidisciplinary team, Head of year 5 medicine.

Public Engagement

• Spoken to the Lupus society patient support group and produced articles for Lupus UK magazine.
• Working with the Lauren Currie Twilight Foundation to establish patient support groups. I spoke at the first of these meetings in February 2012.

Collaborators

• Jeremy Hughes
• Lesley Forrester

Sources of Funding

Kidney Research UK

More information on funding at David Kluth's Research Explorer profile.