Organ failure, such as end stage renal disease, places a substantial burden on the United States healthcare system and transplantation has been shown to be the most cost effective treatment option. Each year, there are nearly 30,000 solid organ transplants (SOTs) performed and Healthy People 2020 has made it a priority to reduce the number of deaths among recipients with a functioning graft. Transplant recipients are given immunosuppressive therapy (IST) to prevent host rejection of the graft. IST may include induction, a monoclonal or polyclonal antibody therapy administered at the time of transplantation to mitigate immediate cellular rejection, in addition to maintenance combination therapy. Although IST has proven effective at preventing rejection, the safety of these therapies needs to be more thoroughly evaluated, as evidence suggests an increased risk of infection associated with IST drugs. Infection may lead to sepsis, or systemic inflammation and organ dysfunction resulting from an infectious process, which can have devastating consequences for patient and graft survival.
The specific aims of this study are to 1.1) determine the association of initial IST with sepsis risk and outcomes (mortality and graft failure) among all SOT recipients using time-to-event analyses that account for confounding by indication; 1.2) determine the association of long- term IST with sepsis risk and outcomes among kidney transplant recipients; 2.1) identify risk factors for sepsis among SOT recipients; 2.2) develop and internally validate sepsis risk prediction tools. In order to complete these aims, we will use 2005-2013 data from the Scientific Registry of Transplant Recipients (SRTR) linked to administrative hospitalization data, and 2008-2013 data from the United States Renal Data System (USRDS) linked to Medicare claims. The SRTR and USRDS collect information on recipients of all organ types and kidney recipients, respectively. These databases contain comprehensive donor and recipient information, including demographics, diagnosis data, biochemical values, and treatment history. SRTR data pertaining to kidney, heart, liver, lung, intestine, and pancreas transplants are collected by the Organ Procurement and Transplantation Network from hospitals and organ procurement organizations. USRDS kidney transplant data originates from a variety of sources, including the Centers for Medicare and Medicaid Services and the United Network for Organ Sharing. We will use USRDS data linked with claims to ascertain more granular pharmacy data that will allow for characterization of long-term IST usage patterns. The resources available through UAB and my mentorship team provide an ideal environment for conducting this study. My mentors have a long track record of successful research in epidemiology, sepsis, nephrology, and transplant medicine. This F31 grant also includes a tailored training program focused on career development, enhancing my analytic skill set, and gaining knowledge related to the care of transplant recipients. The training received through this proposal will allow me to obtain the required skills to achieve my goal of becoming an independent researcher.
Public Health Relevance Statement: Each year, nearly 30,000 solid organ transplants (SOTs) are performed in the United States, and recipients are at increased risk of mortality compared to the general population. Agents used for immunosuppressive therapy (IST) are effective for preventing transplant rejection, but are associated with an increased risk of infectious complications, such as sepsis (infection with systemic inflammation and organ dysfunction). This study could impact public health by identifying risk factors (including specific aspects of IST) for post-transplant sepsis and producing valuable sepsis risk prediction tools for clinicians, ultimately helping to optimize follow-up care by encouraging thorough consideration of IST options, evaluation current prophylaxis protocols, and monitoring of patients with elevated risk profiles.
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