As of May 2020, over five million confirmed cases of COVID-19 have been reported globally with over 400,000 associated deaths. Around 5-20% of patients develop critical illness, which predominantly manifests as acute respiratory distress syndrome. When this develops, the estimated mortality is around 40%, and as high as 80% in ventilated patients. Several early reports describe the development of an excessive inflammatory response, the so-called `cytokine storm', which is strongly associated with rapid deterioration in clinical condition and mortality. Early reports of kidney transplant recipients, who are at high risk due to chronic immunosuppression and additional comorbid diseases, portray a concerning picture. In one series of 36 patients, 39% required mechanical ventilation, 21% required renal replacement therapy, and 28% died. Of the 11 patients that were intubated, 64% died. However, there is still an unmet need of understanding disease natural course, specific risk factors, identifying biomarkers, as well as potential impact of COVID-19 on graft/patient survival in vulnerable KTRs. To fill this information gap, we propose a comprehensive observational analysis of epidemiological factors and immunological assay results in COVID19-infected KTRs at 2 medical centers at the epicenter of COVID19 infection in NYC (Mount Sinai Hospital in Manhattan and Montefiore Hospital in the Bronx). We hypothesize that specific recipient clinical characteristics affect COVID-19 clinical course and that recipient immunosuppression in KTRs alters the ability of COVID-19 KTRs to develop protective anti-COVID-19 humoral and cell-mediated immunity that contributes to the morbidity and mortality of these individuals. We will test this hypothesis by 1) examining risk factors of COVID-19 severity in a large dataset of KTRs and individuals from the general population with COVID-19 (aim 1); 2) by characterizing the COVID-19 reactive humoral and cellular immune response in serially collected samples from COVID-19 KTRs (aim 2); and 3) by comprehensive assessment of DNA and serial serum, RNA, and PBMC from COVID-19 KTRs to identify disease mechanisms and potentially informative biomarkers for outcomes (aim 3). The proposed work is significant because of the high incidence of the disease, rate of community transmission, high mortality, and absence of clearly effective therapeutic options. Our studies will be amongst the first to define risk factors, predictors, and pathogenic mechanisms of COVID-19 in Kidney transplantation and may apply to recipients of other transplanted organs, as well as to individuals on chronic immunosuppression due to autoimmune diseases.
In this application we propose to study COVID-19 disease from SARS-CoV-2 virus in the unique risk population of Kidney transplant recipients. Using data and bio-samples from two hospital systems at the forefront of this pandemic and the highest COVID-19 case loads, we wil identify clinical and biomarker risk profiles for disease severity in transplant patients with COVID disease. In addition, we will use novel assays for humoral and cell-mediated immunity to study COVID immune responses in these immunosupppressed patients and compare with controls.
|Heeger, Peter S (2018) Response to Commentary. Transplantation 102:e368-e369|
|Faddoul, Geovani; Nadkarni, Girish N; Bridges, Nancy D et al. (2018) Analysis of Biomarkers Within the Initial 2 Years Posttransplant and 5-Year Kidney Transplant Outcomes: Results From Clinical Trials in Organ Transplantation-17. Transplantation 102:673-680|
|D'Addio, Francesca; Vergani, Andrea; Potena, Luciano et al. (2018) P2X7R mutation disrupts the NLRP3-mediated Th program and predicts poor cardiac allograft outcomes. J Clin Invest 128:3490-3503|
|Asare, A; Kanaparthi, S; Lim, N et al. (2017) B Cell Receptor Genes Associated With Tolerance Identify a Cohort of Immunosuppressed Patients With Improved Renal Allograft Graft Function. Am J Transplant 17:2627-2639|
|Fishman, Jay A; Iklé, David N; Wilkinson, Robert A (2017) Discrepant serological assays for Pneumococcus in renal transplant recipients - a prospective study. Transpl Int 30:689-694|
|Weigt, S Samuel; Palchevskiy, Vyacheslav; Belperio, John A (2017) Inflammasomes and IL-1 biology in the pathogenesis of allograft dysfunction. J Clin Invest 127:2022-2029|
|Gandolfini, Ilaria; Harris, Cynthia; Abecassis, Michael et al. (2017) Rapid Biolayer Interferometry Measurements of Urinary CXCL9 to Detect Cellular Infiltrates Noninvasively After Kidney Transplantation. Kidney Int Rep 2:1186-1193|
|Crespo, Elena; Cravedi, Paolo; Martorell, Jaume et al. (2017) Posttransplant peripheral blood donor-specific interferon-? enzyme-linked immune spot assay differentiates risk of subclinical rejection and de novo donor-specific alloantibodies in kidney transplant recipients. Kidney Int 92:201-213|
|Menon, Madhav C; Murphy, Barbara; Heeger, Peter S (2017) Moving Biomarkers toward Clinical Implementation in Kidney Transplantation. J Am Soc Nephrol 28:735-747|
|Javaheri, Ali; Molina, Maria; Zamani, Payman et al. (2016) Cholesterol efflux capacity of high-density lipoprotein correlates with survival and allograft vasculopathy in cardiac transplant recipients. J Heart Lung Transplant 35:1295-1302|
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