*Purpose: Infections remain a major threat to successful kidney transplantation (KT), and are associated with a subsequent higher risk of mortality and graft loss. However, changes in recipient/donor demographics, allocation policy, immunosuppressive regimens, and clinical protocols over the last decade might have altered the incidence and impact of post-KT infections.

*Methods: To characterize temporal changes in the incidence and impact of post-KT infections, we used national data from the United States Renal Data System to study 141,664 Medicare-primary KT recipients from 1/1/1999-12/31/2014, with linkage to Scientific Registry of Transplant Recipients for accurate ascertainment of mortality and graft loss. Infection diagnoses were ascertained by ICD-9 codes. We used adjusted multi-level logistic regression to quantify temporal trends in the likelihood of developing a post-KT infection, after accounting for transplant center-level variation. We then used adjusted multi-level Cox regression to characterize temporal trends in the impact of a post-KT infection on post-transplant mortality and graft loss, treating a post-KT infection as a time-varying exposure.

*Results: Although 63.6% of all KT recipients developed a post-KT infection, this decreased from 73.2% of those in 1999-2002 to 49.0% of those in 2011-2014. After accounting for recipient, donor, and transplant-related characteristics, the likelihood of a post-KT infection decreased over time. Compared to KT recipients in 1999-2002, the likelihood of a post-KT infection was 22% lower for recipients in 2003-2006 (adjusted odds ratio [aOR]: _0.740.78_0.83, p<0.001), 36% lower for recipients in 2007-2010 (aOR: _0.590.64_0.69, p<0.001), and 69% lower for recipients in 2011-2014 (aOR: _0.280.31_0.34, p<0.001). Similarly, the impact of a post-KT infection on mortality attenuated over time. The mortality risk attributable to a post-KT infection was 12% lower in 2011-2014 compared to 1999-2002 (interaction ratio: _0.820.88_0.95, p<0.001). In other words, a post-KT infection was associated with a 2.12-fold higher mortality risk in 1999-2002 (adjusted hazard ratio [aHR]: _2.022.12_2.22, p<0.001), whereas it was associated with only a 1.87-fold higher mortality risk in 2011-2014 (aHR: _1.761.87_1.98, p<0.001). However, the impact of a post-KT infection on graft loss did not change over time (p=0.2), and remained associated with a 1.79-fold higher risk of graft loss (aHR: _1.691.79_1.90, p<0.001) across all eras.

*Conclusions: The incidence and mortality risk attributable to post-KT infections has decreased over time, although post-KT infections remain common and a major driver of poor post-KT outcomes. Immunosuppression choices should be carefully tailored accordingly, especially in those at higher risk of infection.

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