Peritoneal Immunity Group

Renal replacement therapy is a chronic condition associated with significant morbidity and mortality and requires daily therapeutic intervention.

While there remains no cure for renal deterioration and the number of available kidney donors is limited, chronic dialysis remains an essential daily life-saving treatment modality.

Treatment with Peritoneal Dialysis (PD) offers significant treatment, lifestyle, and quality of life advantages over hospital haemodialysis.

In addition, it is a more cost-effective therapy. The “Achilles’ heel” of PD, however, remains the susceptibility to recurrent infection with detrimental effects on the process of dialysis through direct membrane damage, but also in more severe infection through significant morbidity and mortality.

Over the past decade there has been a shift in infection profiles towards more virulent infections and an increased prevalence of antibiotic resistance. This, together with the already unacceptable cure and relapse rates, and concomitant morbidity and mortality represent significant limitations to PD therapy.

As we approach the post-antibiotic era there is a clear need for novel therapies to fight infections by resistant strains and improve patient outcomes. If we are to limit the susceptibility to infection and the detrimental impact of prolonged inflammation on membrane longevity, we need to better understand the processes causing deleterious alterations to the peritoneal immune response.

The peritoneal cavity in PD serves as unique window to inflammatory scenarios that can be prospectively observed in vivo. It affords easy, continuous access to all relevant cellular and humoral players, and allows us to examine how treatment and infection modulate these processes. We know of no other experimental model that gives such direct insight into human immune responses in a similarly clinically relevant, convenient, non-invasive manner.

Research

The main focus of research remains the mechanisms controlling leukocyte recruitment and clearance during inflammation. The initial focus has been on acute inflammation and defining those factors that govern resolution of inflammation.

Over the next years the focus of our work will be in examining the mechanisms by which resolving acute inflammation becomes manifested as chronic inflammation characterized by deregulated leukocyte trafficking and activation.

With this latter aim in mind we have recently developed a flare model of peritoneal inflammation that has provided clear evidence of a chronic inflammatory phenotype being developed as a result of repeated inflammatory hits.

These data parallel our clinical observations of deregulated IL-6 signalling in PD patients with a history of infection. Given the presumed importance of IL-6 signalling in many of these processes these studies will use both IL-6 deficient mice as well as conditional mutants of the JAK-STAT signaling cascade to dissect these events.

Projects

PERIT-PD: Patient immune responses to infection in Peritoneal Dialysis

Peritonitis remains the main reason for treatment failure in peritoneal dialysis (PD) patients. Despite this the peritoneal immune response to specific pathogens remains poorly defined.

This project intends to collect a large number of defined samples from patients to characterise the immune response and use this to develop potential methods for better diagnosis, treatment and monitoring of infection in these patients.

EuTRiPD: European Training & Research in Peritoneal Dialysis

https://www.youtube.com/watch?v=WFlA9IkH9EU

Long term clinical studies in peritoneal dialysis

Our long term strategy is to have a better understanding of the natural history of the structural and functional alterations that occur in the peritoneum of peritoneal dialysis patients, limiting time on therapy.

The Biopsy Registry

An international observational study, with collections in the UK, France, Spain and Japan providing samples of dialysed peritoneum for analysis.

The Global Fluid Study

Established in 2001 and is endorsed by the International Society for Peritoneal Dialysis (ISPD) and the British Renal Society (BRS) and supported by Baxter Healthcare, Renal Division. This study has established collection of dialysis effluent and plasma and clinical data from ~2000 incident PD in centres in the UK, Korea, Israel, Belgium and Canada. This will allow us to assess longitudinally how changes in biomarker signatures relate to peritoneal membrane longevity and inflammation and outcomes in PD patients.

To complement GLOBAL and to specifically address the issue of Encapsulating Peritoneal sclerosis, we have also established the Japan Fluid Study (JFS) funded by Baxter Japan Ltd. This is aimed at evaluating both clinical and changes in effluent markers in ~450 long-term (>4 years on therapy) PD patients. This study is linked with the International EPS DNA Bank: Genetic Markers of EPS in Peritoneal Dialysis, a partner in ReGeNet.