Case study: Kidney transplant patient with COVID-19: impact of viral infection on background cell-free DNA in a donor-derived cell-free DNA rejection assay

ABSTRACT

Introduction: Donor-derived cell-free DNA (dd-cfDNA) assays are clinically validated to detect kidney transplant injury, reporting the donor fraction as a percentage of the total, or background, cfDNA. Various clinical factors can cause a significant increase in recipient cfDNA, contributing to higher background cfDNA and lower donor fraction, which may result in a false negative test result. Case Description A 50+ year old woman with end-stage renal disease secondary to polycystic kidney disease presented with 4 days (d) of diffuse muscle pain at 11 months post-kidney transplant. In the emergency department she had a fever to 101°F, bilateral infiltrates on chest x-ray, and a positive COVID-19 (SARS-CoV-2) test. She remained febrile for 3d before developing acute respiratory distress requiring oxygen supplementation;her creatinine level was 3 mg/dL. Due to worsening of her respiratory status, she was intubated and started empirically on vancomycin, meropenem, and azithromycin;mycophenolate mofetil was discontinued. She rapidly progressed to septic shock requiring vasopressor therapy. Her renal function deteriorated, and she was started on continuous renal replacement therapy on hospital d7. She received leronlimab on hospital d7 and d14 and convalescent plasma on hospital d11. Tacrolimus was discontinued on hospital d10 and she continued prednisone at 5 mg/d. Dd-cfDNA testing to assess allograft injury and to rule out active rejection was performed. At hospital d20, her dd-cfDNA was 0.07% with an elevated background cfDNA of 28,569 arbitrary units (AU, ∼57X median value). At the second blood draw at hospital d25, her dd-cfDNA was 0.25% with a background cfDNA level reduced to 7,503 AU (∼15X median value). Discussion: In this case, infection with the SARS-CoV-2 virus was associated with a very elevated background cfDNA level, likely due to cellular apoptosis due to the immune process and/or tissue ischemia due to sepsis-associated hypoperfusion. Although this patient was not known to have active rejection of her allograft, the very high background levels complicate the interpretation of results, especially when donor fraction were reported.