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Advisory Committee Chair

Gerald McGwin Jr

Advisory Committee Members

Paul Muntner

Paul A Maclennan

Roslyn B Mannon

Henry E Wang

Document Type

Dissertation

Date of Award

2018

Degree Name by School

Doctor of Philosophy (PhD) School of Public Health

Abstract

Solid organ transplant (SOT) recipients typically need immunosuppressive therapy (IST) to protect graft function and regimens may include an induction agent (e.g., anti-thymocyte globulin [ATG] or alemtuzumab) with maintenance medications (e.g., tacrolimus, mycophenolate mofetil [MMF], mycophenolic acid [MPA], or azathioprine [AZA]). Sepsis, or organ dysfunction resulting from a dysregulated host response to infection, is a common complication among SOT recipients. Using national data from the United States Renal Data System (USRDS), we sought to determine the associations of IST regimens and maintenance medication exposure with sepsis risks and outcomes among kidney transplant recipients (KTRs). Using USRDS and single center data, we also constructed sepsis risk prediction tools for KTRs and all SOT recipients combined. For the first study, among 82,051 adult KTRs in the USRDS transplanted over 2004-2013, ATG+tacrolimus+MMF/MPA/AZA+corticosteroids was the most common IST regimen (24.8%). Corticosteroid-sparing regimens with ATG and alemtuzumab showed lower sepsis risk (hazard ratio [HR] 0.83; 95% confidence interval [CI] 0.77-0.90 and HR 0.87; CI 0.80-0.95, respectively) relative to the ATG-based regimen with corticosteroids. For events ≥6 months post-transplant, the alemtuzumab-based regimen without corticosteroids showed higher 90-day mortality (HR 1.50; CI 1.10-2.05). For the second study, 27,898 KTRs in the USRDS filled at least one prescription for tacrolimus and 28,927 filled a prescription for MMF/MPA. Nonadherence (proportion of days covered <0.7) was associated with higher sepsis risk for tacrolimus (HR 1.17; CI 1.06-1.29) and MMF/MPA (HR 1.28; CI 1.16-1.41). Discontinuation was also associated with increased risks of sepsis for tacrolimus (HR 1.56; CI 1.37-1.78) and MMF/MPA (HR 1.64; CI 1.46-1.84). Discontinuation was associated with higher risk of 90-day mortality following sepsis for MMF/MPA (HR 1.53; CI 1.08-2.15). For the third study, a total of 61,538 KTRs from the USRDS were included in the derivation data set and 2,994 recipients of kidney, liver, heart, or lung transplants at University of Alabama at Birmingham hospital over 2007-2015 were included in the hospital database. The model for explicitly-coded sepsis among KTRs was well-calibrated and demonstrated modest discrimination in the hospital database (C-index 0.672; CI 0.617-0.726). For all SOT recipients in the hospital database, models over predicted sepsis risks and the model for explicitly-coded sepsis had modest discrimination (corrected C-index 0.674). Our studies identified populations of SOT recipients at heightened risk of sepsis and poor outcomes following sepsis. We also produced models for predicting sepsis risk within three years post-transplant.

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