Approximately 500,000 individuals in the United States require kidney replacement therapy for end-stage renal disease (ESRD), and over $40 billion are annually spent in hemodialysis (HD) and kidney transplant treatments for these patients. Despite improvements in the HD technology, the mortality rate of HD patients is still exceptionally high, with a 5-year survival rate of only 35%. Patients succumb to conditions that result from the chronic inflammation caused by contact of the blood with the HD filters. This blood-filter interaction can activate the complement system, which is a strong mediator of inflammatory processes. Although kidney transplantation provides improved quality of life and survival rates over dialysis, the organ shortage and compatibility issues limit the number of transplants performed worldwide. Also, the period of cold ischemia observed during organ collection induces the activation of complement and inflammation, contributing to graft rejection and loss in approximately 4% of the transplanted patients. Thus, inflammatory immune responses are involved in several aspects of HD- and transplantation-related complications. Notably, recent reports indicate promising effects of therapeutic inhibition of complement by modulating inflammatory responses during HD and transplantation. This proposal therefore presents a comprehensive study to investigate complement-mediated inflammatory mechanisms induced during HD and kidney transplantation and evaluates a panel of complement inhibitors for their ability to attenuate such inflammatory processes.
Aim 1 will use an established extracorporeal circulation model in combination with biochemical, proteomic, and cellular assays to dissect the complement pathways and effectors involved in the HD procedure and the inflammatory networks triggered. The evaluation of blood from ESRD patients and the establishment of an in vivo HD model in non-human primates will enhance the applicability of the results from this aim to clinical situations.
In Aim 2, similar biochemical and cellular assays will be used to dissect the complement pathways and effectors involved during kidney ischemia and reperfusion, and the clinical potential of the complement inhibitor compstatin to prevent organ rejection will be evaluated in an established non-human primate model of ABO-incompatible kidney transplantation. The results obtained are expected to: 1) provide a broad insight into the impact of individual complement pathways and associated effector networks on the detrimental processes that contribute to morbidity and mortality in HD and transplant patients, and 2) arrive at potent and cost-effective treatment options for chronic inflammatory conditions in HD and kidney transplant patients through the inhibition of complement.
The objectives of this proposal are to 1) dissect the mechanisms by which the complement system regulates and promotes inflammation during the treatment of kidney disease, and 2) use appropriate complement inhibitors as rational therapeutic interventions in animal models of hemodialysis, renal transplantation, and ischemia-reperfusion injury. This study will facilitate the development of innovative treatment modalities for
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