Blood Transcriptomes of SARS-CoV-2–Infected Kidney Transplant Recipients Associated with Immune Insufficiency Proportionate to Severity

Abstract

BackgroundAmong patients with COVID-19, kidney transplant recipients (KTRs) have poor outcomes compared with non-KTRs. To provide insight into management of immunosuppression during acute illness, we studied immune signatures from the peripheral blood during and after COVID-19 infection from a multicenter KTR cohort.MethodsWe ascertained clinical data by chart review. A single sample of blood was collected for transcriptome analysis. Total RNA was poly-A selected and RNA was sequenced to evaluate transcriptome changes. We also measured cytokines and chemokines of serum samples collected during acute infection.ResultsA total of 64 patients with COVID-19 in KTRs were enrolled, including 31 with acute COVID-19 (<4 weeks from diagnosis) and 33 with post-acute COVID-19 (>4 weeks postdiagnosis). In the blood transcriptome of acute cases, we identified genes in positive or negative association with COVID-19 severity scores. Functional enrichment analyses showed upregulation of neutrophil and innate immune pathways but downregulation of T cell and adaptive immune activation pathways. This finding was independent of lymphocyte count, despite reduced immunosuppressant use in most KTRs. Compared with acute cases, post-acute cases showed “normalization” of these enriched pathways after 4 weeks, suggesting recovery of adaptive immune system activation despite reinstitution of immunosuppression. Analysis of the non-KTR cohort with COVID-19 showed significant overlap with KTRs in these functions. Serum inflammatory cytokines followed an opposite trend (i.e., increased with disease severity), indicating that blood lymphocytes are not the primary source.ConclusionsThe blood transcriptome of KTRs affected by COVID-19 shows decreases in T cell and adaptive immune activation pathways during acute disease that, despite reduced immunosuppressant use, associate with severity. These pathways show recovery after acute illness.

Rationale and Design of a Phase 2, Double-blind, Placebo-Controlled, Randomized Trial Evaluating AMP Kinase-Activation by Metformin in Focal Segmental Glomerulosclerosis

“…These will serve as biomarkers indicating treatment responsiveness. 61 , 62 , 64 , 68 Biomarkers identified at baseline can enrich participation, help risk stratification, whereas those that associate with treatment responsiveness can reduce duration or costs in subsequent FSGS trials. 64 , 69 , 70 …”

COVID-19 in kidney transplantation-implications for immunosuppression and vaccination

“…Decreased immunosuppression is generally not associated with increased rejection. In a study of 64 KTRs with COVID-19, 31 with acute COVID-19 (<4 weeks from diagnosis) and 33 with post-acute COVID-19 (>4 weeks postdiagnosis) blood transcriptomes were examined ( 60 ). The authors reported upregulation of neutrophil and innate immune pathways but downregulation of T cell and adaptive immune activation pathways with acute infection.…”

Omicron induced distinct immune respiratory transcriptomics signatures compared to pre‐existing variants in critically ill COVID‐19 patients

“…First, the comparison of hospitalized patients during different epidemic waves is subject to several confounding and historical biases, including the use of corticosteroids and anti-IL-6 antagonists (i.e., tocilizumab), and evolution of the clinical context, notably the increasing role of immunodepression in the severity of the disease 12. Furthermore, previous transcriptomicsbased studies highlighted the impact of vaccination and immunosuppression on the immune response of COVID-19 patients [46][47][48]. However, the unsupervised analysis of the entire cohort did not show any impact of the immunocompromised or vaccinated status on the distribution of the transcriptomic data.…”