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Development of a point-of-care microfluidics platform to monitor kidney transplant rejection
Kidney transplantation, in comparison to dialysis, offers substantial survival and quality of life benefits for patients with end-stage renal disease and is a highly cost-effective treatment. However, innovations to improve long-term function of kidney transplants have been limited and long-term survival of transplants has remained largely unchanged for the last two decades. Acute rejection (AR), due to the immunological barrier between donor and recipient, can lead to chronic damage and is a major cause of long-term failure of renal transplants. Forty percent of transplanted kidneys are lost within 10 years, with patients returning to dialysis and possibly dying whilst waiting for a new kidney. Long-term kidney transplant function is beneficial for both patients (because mortality and quality of life is lower than with maintenance dialysis) and health-care providers (because the annual cost of transplantation is substantially less than that of dialysis). Monitoring of renal transplant patients is an important part of post-transplantation management, with allograft dysfunction mainly relying on detecting changes to serum creatinine (sCr) levels. Serum Cr levels however typically do not increase in the early stages of graft injury, and is, therefore, not a sensitive test to detect early AR which may lead to chronic irreversible damage. To distinguish AR from other causes of graft function decline, a percutaneous needle graft biopsy still remains the golden standard modality of investigation, but it is an invasive procedure requiring hospital admission. Therefore, identification and validation of non-invasive biomarkers, which accurately predict or exclude the presence of AR, would improve therapeutic decision making, and is a critical priority for the transplantation community. In AR, graft-reactive cells gain access to the urinary space and therefore urine represents an appropriate biospecimen to investigate graft destructive immunity. Urinary chemokines, which are produced by inflammatory cells, represent one of the most potential useful markers and can identify renal transplant recipients with histological evidence of suspicious and/or borderline AR. In particular, observational studies have shown that selective urinary chemokines (CXCL9 and CXCL10) outperform standard post- transplant surveillance by detecting subclinical rejection and early clinical AR before graft functional decline is clinically apparent. However, routine testing of urinary chemokines is not performed and the long turn-around time for such an assessment with currently available techniques is not suited for clinical uptake. As a result, these assays have not moved from the research arena to a clinically implementable testing strategy that could guide therapeutic decision making. We propose to develop a novel microfluidics-based point-of-care device to rapidly, accurately, and non- invasively monitor urinary CXCL9 and CXCL10 serially in renal transplant recipients, suitable for use in an out-patient setting, and identify recipients with incipient AR. The pilot work in this project will hopefully lead to prospective urinary chemokine-based monitoring trials to inform both the clinical utility and implementation of our novel non-invasive surveillance platform. Such a development could potentially pave the way for personalized management of renal transplant recipients, allow for modulation of short- and long-term maintenance immunosuppression, and ultimately lead to improved graft survival.
4 Researchers
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