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Biomarkers of Cytokine Release Syndrome Predict Disease Severity and Mortality From COVID-19 in Kidney Transplant Recipients

Our take —

This case series followed 49 patients with a history of kidney transplant who contracted COVID-19 in Alsace, France at the beginning of the pandemic. No patients lost their grafted kidneys, but 9 patients died. High levels of all measured inflammatory markers were significantly associated with mortality. Though limited by its small sample size, lack of a control group, and variable treatment strategies, this study is a starting point for research on the impact of COVID-19 among individuals with kidney transplant.

Study design

Case Series

Study population and setting

This case series followed 49 patients with a history of kidney transplantation who presented to a hospital in Alsace, France between March 4 and April 7, 2020 with evidence ofSARS-CoV-2 infection by PCR, imaging consistent with COVID-19, and/or high clinical suspicion for COVID-19. Medical record data were collected daily from admission and included demographics, COVID-19 presentation, laboratory values, medications, and imaging until April 30, 2020. The authors were primarily interested in the following predefined outcomes: death, intensive care unit admission, acute kidney injury, graft loss, venous thrombotic events, and neurologic or cardiac complications. Patients were categorized with 1) mild COVID-19 (outpatient), 2) non-severe COVID-19 (hospitalized with <6L/min supplemental oxygen), and 3) severe COVID-19 (hospitalized and > 6L/min supplemental oxygen), and continuous covariates were tested for association with these outcomes using Mann-Whitney tests and Spearman’s correlation coefficients. Finally, the authors analyzed time to severe COVID-19 and time to COVID-19 death using Kaplan-Meier curves among hospitalized patients with non-missing data. Log-rank tests were used to compare estimated survival for patients with different dichotomized values of c-reactive protein, interleukin-6, lactate dehydrogenase, high sensitivity troponin, D-dimer, and fibrinogen. Receiver operating characteristic (ROC) curves were based on dichotomized levels of these biomarkers.

Summary of Main Findings

The median time between kidney transplant and COVID-19 symptom onset among the 49 included patients was 7.1 years (interquartile range 2.9-14.4 years). Most patients were white (98%), male (76%), and/or over 60 years (55%). The 8 patients with mild COVID-19 were, on average, younger, had a lower median body mass index, and were more likely to be treated with mTOR inhibitors than the 41 hospitalized patients (21 non-severe, 20 severe). A majority of hospitalized patients were obese (51%). On admission, mycophenolate mofetil/mycophenolic acid and mTOR inhibitors were discontinued, and calcineurin inhibitors were temporarily withdrawn in 15 (36.6%) patients. Among all hospitalized patients, there were no graft failures, 14 (34%) patients were admitted to the intensive care unit, 16 (39%) experienced mild-to-severe neurologic complications, 1 experienced deep vein thrombosis, 1 experienced myocarditis, 31 (76%) experienced acute kidney injury (23 of whom recovered), and 9 (22%) patients died. Patients with severe COVID-19 were more likely to be obese, to have shortness of breath rather than diarrhea, and to have lower arterial oxygen levels and higher c-reactive protein, interleukin-6, and high sensitivity troponin on admission. High levels of all measured inflammatory markers were significantly associated with mortality via the log-rank test.

Study Strengths

This study focused on an understudied population during the COVID-19 pandemic: those with a history of a kidney transplant.

Limitations

This study was limited by its small sample size and a lack of a control group, which makes it hard to generalize to other individuals with a history of a kidney transplant, and precludes comparison with other COVID-19 patients. Almost by definition, patients with a history of kidney transplantation have a complicated medical history that may include diabetes, obesity, hypertension, and other comorbidities, which makes it difficult to home in on the added COVID-related risks posed by a grafted kidney and the necessary chronic immunosuppression. Furthermore, since this study was conducted early in the pandemic, participants received a wide variety of treatments, most of which have since been found ineffective against COVID-19 in large randomized trials. This makes it difficult to assess how individuals with a history of a kidney transplant might fare if they contracted COVID-19 at a later date. Finally, the authors dichotomized laboratory values to create Kaplan-Meier curves, which likely results in residual confounding.

Value added

This study provides some insight into the implications of COVID-19 for patients with a history of a kidney transplant. Importantly, none of the included patients lost their grafted kidney.

This review was posted on: 19 November 2020