Peripheral immune profiles and renal impairment parameters synergistically predict fatal SARS-CoV-2 infection in a kidney transplant cohort

Introduction: Lifelong immunosuppression in kidney transplant recipients (KTRs) preserves graft survival but concurrently increases susceptibility to life-threatening viral infections such as SARS-CoV-2. However, the peripheral immune phenotype associated with increased mortality in the context of immunosuppression remains uncharacterized, and the synergistic prognostic value of this phenotype­—when combined with established biomarkers including inflammatory cytokines and clinical baseline parameters – for mortality risk stratification remains unexplored. This critical knowledge gap hinders timely adjustment of immunosuppression regimens.
Methods: Using SARS-CoV-2 as an infection model to identify peripheral immune signatures associated with fatal infection in KTRs, we conducted integrated immune profiling – combining high-dimensional mass cytometry (CyTOF) and multiplex cytokine analysis – on a cohort of 59 KTRs diagnosed with COVID-19, among whom 15 developed severe disease, including 8 with a  fatal outcome. To characterize the immunological trajectory of disease progression, we first identified correlates of severity, and then specifically interrogated the features distinguishing fatal cases within the severe group, and finally validated these signatures in the fatal outcome across the entire cohort. The identified immune subset signatures were further benchmarked against external CyTOF datasets from non-COVID-19 KTRs (n = 19) and immunocompetent COVID-19 patients (n = 16). Predictive models incorporating immune subsets, cytokines, and clinical covariates were constructed to evaluate their prognostic values for fatal outcome.
Results: In KTRs with COVID-19, we identified a mortality-associated immune phenotype affected by immunosuppression, characterized by a convergent collapse of naïve T cells during disease progression, and a mortality-specific loss of a protective CD8+ effector T cell subset. Furthermore, the fatal outcome was also characterized by convergent elevation of inflammatory cytokines (IL-2, IL-6, IL-8, IL-10) and a specific reduction in IFN-α, alongside renal impairment during infection. Critically, predictive models integrating these multi-tiered biomarkers achieved superior prognostic performance compared to single-tier approaches, underscoring the synergistic value of combining baseline clinical risk with dynamic immune indicators for mortality risk stratification.
Conclusions: Re-programmed peripheral T cell landscapes, distinct cytokine profiles, and baseline clinical factors collectively predict fatal COVID-19 outcome in KTRs. This integrated prognostic model enables pre-emptively identification of high-risk patients for aggressive intervention and immunosuppression management during future viral infection outbreaks in this vulnerable population.