This proposal seeks to establish levels of circulating endothelial microparticles (EMP) as a novel biomarker of allograft rejection in the setting of kidney transplantation. Endothelial cells (EC) play an important role in the pathogenesis of allograft dysfunction and rejection. With improved immunosuppression and surgical technique, graft survival has significantly increased. Nevertheless, allograft rejection remains one of the main causes for allograft failure. The endothelium is one of the main targets in allograft rejection, especially antibody-mediated rejection (AMR). Typically, renal allograft function is evaluated by serum creatinine (SC) levels. Unfortunately, SC level elevation is a non-specific marker of renal allograft dysfunction, and it may occur in many different conditions. The "gold standard" test for the assessment of allograft rejection is renal allograft biopsy, which is an invasive, expensive and relatively risky procedure. The patterns of acute cellular rejection (ACR) are well-documented and broadly recognized. However, diagnosis of AMR is one of the most challenging in renal pathology. Peritubular capillary (PTC) C4d staining is one of the markers of AMR. Still, some kidney biopsies show C4d staining without histologic findings of AMR or ACR. Recently, evidence that some forms of AMR may be negative for PTC C4d staining has been described. Based on these data, the need for a reliable and clinically significant marker of allograft rejection is emerging. Microparticles are small membrane vesicles shed by different cell types, which contain cell surface proteins and cytoplasmic components of the original cell. The microparticle production is a part of normal cell function, but it increases by apoptotic cells and cells under stress. Others and we had previously demonstrated that levels of circulating EMP may be used as a surrogate marker of EC dysfunction. Recent studies have indicated changes in circulating EMP levels in patients with solid organ transplants, including kidneys. We demonstrated that circulating EMP levels, initially elevated in patients with Hepatitis C cirrhosis, were decreased to the levels seen in healthy people two weeks after liver transplantation. This data suggests that the levels of circulating EMP may be useful as a biomarker of EC function in patients with solid organ transplants. Based on these findings, we hypothesize that 1) an elevation in circulating EMP levels may be a novel marker of renal allograft rejection;2) EMP produced by the renal allograft endothelium are different by their protein composition from EMP produced by the recipient endothelium;therefore, the former may be used as the biomarker of EC function of the renal allograft. Our hypotheses will be tested under two specific aims: 1) evaluate if the levels of circulating endothelial microparticles can be used as a marker of allograft rejection in patients with kidney transplants;2) undertake a pilot study to investigate if the pool of circulating EMP may be further separated in order to distinguish between the microparticles produced by the recipient and allograft endothelium. Conclusions: This R21 is the essential step to advance the study of EMP as the novel marker of rejection in renal transplant patients.

Public Health Relevance

Renal transplantation saves thousands of lives and improves quality of life in patients with end stage renal disease. The main cause of renal allograft failure is rejection. The endothelium is the internal layer in blood vessels and it is one of the main targets during allograft rejection. Microparticles are small vesicles shed by many cells when they are functioning abnormally, including the endothelium. We described earlier that the number of endothelial microparticles reflects endothelial cell function in experimental settings in vitro and in animals. We propose that number of microparticles shed by the endothelium in the renal allograft increases during rejection and this may be used as a novel marker for rejection. Our long term goal is to develop a novel, reliable and useful clinical test to recognize rejection in patients with renal transplants.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Exploratory/Developmental Grants (R21)
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Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
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Kimmel, Paul
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Ohio State University
Schools of Medicine
United States
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Qamri, Zahida; Pelletier, Ronald; Foster, Jamison et al. (2014) Early posttransplant changes in circulating endothelial microparticles in patients with kidney transplantation. Transpl Immunol 31:60-4