key: cord-0724653-p2lwocse
authors: Cravedi, Paolo; Mothi, Suraj S.; Azzi, Yorg; Haverly, Meredith; Farouk, Samira S.; Pérez‐Sáez, María J.; Redondo‐Pachón, Maria D.; Murphy, Barbara; Florman, Sander; Cyrino, Laura G.; Grafals, Monica; Venkataraman, Sandheep; Cheng, Xingxing S.; Wang, Aileen X.; Zaza, Gianluigi; Ranghino, Andrea; Furian, Lucrezia; Manrique, Joaquin; Maggiore, Umberto; Gandolfini, Ilaria; Agrawal, Nikhil; Patel, Het; Akalin, Enver; Riella, Leonardo V.
title: COVID‐19 and kidney transplantation: Results from the TANGO International Transplant Consortium
date: 2020-08-04
journal: Am J Transplant
DOI: 10.1111/ajt.16185
sha: 65f4ef07be0064b9f70265f9ee83e20286d2384b
doc_id: 724653
cord_uid: p2lwocse

Kidney transplant recipients may be at a high risk of developing critical coronavirus disease 2019 (COVID‐19) illness due to chronic immunosuppression and comorbidities. We identified hospitalized adult kidney transplant recipients at 12 transplant centers in the United States, Italy, and Spain who tested positive for COVID‐19. Clinical presentation, laboratory values, immunosuppression, and treatment strategies were reviewed, and predictors of poor clinical outcomes were determined through multivariable analyses. Among 9845 kidney transplant recipients across centers, 144 were hospitalized due to COVID‐19 during the 9‐week study period. Of the 144 patients, 66% were male with a mean age of 60 (±12) years, and 40% were Hispanic and 25% were African American. Prevalent comorbidities included hypertension (95%), diabetes (52%), obesity (49%), and heart (28%) and lung (19%) disease. Therapeutic management included antimetabolite withdrawal (68%), calcineurin inhibitor withdrawal (23%), hydroxychloroquine (71%), antibiotics (74%), tocilizumab (13%), and antivirals (14%). During a median follow‐up period of 52 days (IQR: 16‐66 days), acute kidney injury occurred in 52% cases, with respiratory failure requiring intubation in 29%, and the mortality rate was 32%. The 46 patients who died were older, had lower lymphocyte counts and estimated glomerular filtration rate levels, and had higher serum lactate dehydrogenase, procalcitonin, and interleukin‐6 levels. In sum, hospitalized kidney transplant recipients with COVID‐19 have higher rates of acute kidney injury and mortality.

Since its initial detection in Wuhan, China, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which is responsible for coronavirus disease 2019 (COVID- 19) , has rapidly emerged as an international pandemic. 1, 2 As of June 2020, > 6 million cases have been reported worldwide, leading to > 400 000 deaths. Clinical symptoms associated with COVID-19 are vary, although the most common include fever, cough, shortness of breath, diarrhea, anosmia, and lack of taste. 2 Those with advanced age and medical comorbidities, including diabetes mellitus, hypertension, cardiovascular disease, pulmonary disease, and malignancy, are at increased risk for severe disease, including pneumonia, acute respiratory distress syndrome, septic shock, multiorgan failure, and death. 3, 4 In addition, a hyperinflammatory state, known as cytokine storm syndrome, has been described with COVID-19 infection that is associated with rapidly worsening clinical features leading to multiorgan failure. 5 Increased levels of circulating inflammatory cytokines, including interleukin (IL)-1, IL-6, and interferon-γ have been shown in those patients. 2, 4, 5 Theoretically, solid organ transplant recipients are at particularly higher risk of developing critical COVID-19 due to chronic immunosuppression. European experience in Italy regarding 20 kidney transplant recipients with COVID-19 pneumonia documented a fast progression in > 75% of their patients with 25% mortality during a median follow-up of 7 days. 6 In Spain, 18 solid organ recipients diagnosed with COVID-19 had a mortality rate of 28%. 7 In the United States, the initial experience was reported by transplant centers in New York. A single-center experience at Montefiore Medical Center reported 28% mortality in 36 consecutive adult kidney transplant recipients. 8 Seventy-eight percentage required hospital admission, 96% of hospitalized patients had imaging findings of viral pneumonia, 39% required mechanical ventilation, and 21% required renal replacement therapy. 8 Columbia and Cornell medical centers in New York reported clinical outcomes of 90 transplant recipients (46 kidney, 17 lung, 13 liver, 9 heart, and 5 dual-organ transplants). 9 Among the 68 hospitalized patients, 12% required nonrebreather and 35% required intubation. Sixteen patients died (18% overall, 24% of hospitalized, 52% of ICU patients) and 37 (54%) were discharged. Northwell center reported 30% mortality and 50% acute kidney injury in 10 kidney transplant recipients. 10 The aim of our report is to present the clinical outcomes of a large multicenter cohort of 144 kidney transplant recipients who were hospitalized due to COVID-19 at 12 transplant centers in North America and Europe to identify predictors of poor clinical outcomes.

This retrospective cohort study included kidney transplant recipients admitted with COVID-19 in 12 centers participating in the international TANGO consortium (www.tango xstudy.com). 1 We included all adult (≥18 years) kidney transplant recipients with a functioning kidney allograft who were admitted to a hospital between March 2 and May 15, 2020. Medical records were reviewed by TANGO investigators in the collaborating centers. Since testing criteria for SARS-CoV-2 vary among locations, we decided to exclude patients with presumed or diagnosed COVID-19 who did not require hospital admission. We also excluded any patients who had been reported in prior publications by any of the participating centers. The study was approved by the Brigham and Women's Hospital Research Ethics Commission (2015P000993).

Epidemiological, demographic, clinical, laboratory, treatment, and outcome data were extracted from electronic medical records using were African American. Prevalent comorbidities included hypertension (95%), diabetes (52%), obesity (49%), and heart (28%) and lung (19%) disease. Therapeutic management included antimetabolite withdrawal (68%), calcineurin inhibitor withdrawal (23%), hydroxychloroquine (71%), antibiotics (74%), tocilizumab (13%), and antivirals (14%). During a median follow-up period of 52 days (IQR: 16-66 days), acute kidney injury occurred in 52% cases, with respiratory failure requiring intubation in 29%, and the mortality rate was 32%. The 46 patients who died were older, had lower lymphocyte counts and estimated glomerular filtration rate levels, and had higher serum lactate dehydrogenase, procalcitonin, and interleukin-6 levels. In sum, hospitalized kidney transplant recipients with COVID-19 have higher rates of acute kidney injury and mortality.

clinical research/practice, immunosuppressant, infection and infectious agents -viral, kidney transplantation/nephrology an ad hoc designed data collection form. All data were checked for quality by 2 physicians (Drs Cravedi and Riella) and a researcher (Dr Mothi). 

Descriptive statistics for Table 1 Univariate and multivariate logistic regression models were used to explore associations of baseline laboratory and clinical characteristics and the risk for death. At the outset, it was decided to exclude any COVID-19-related case management characteristics for investigating predictors of survival outcomes (e.g., CNI withdrawal, hydroxychloroquine). Therefore, only clinical or laboratory variables demonstrating significant differences from the baseline were candidates for univariate regression models predicting survival (Table 1) .

With the intention of parsimony due to the limited sample size, we attempted a multivariable risk-prediction model using only 5 vital predictors from the univariable models. Although a strong predictor, dyspnea was excluded due to collinearity with respiratory rate.

Model fit and superiority for the multivariable model were evaluated by using the Akaike information criterion and the Nagelkerke pseudo 

One hundred forty-four kidney transplant recipients with a diagnosis of COVID-19 were identified. Of 144 patients, 95 (66%) were male with a median age of 62 (IQR 52-69) (56.2% > 60) years old, and 40% were Hispanic, 31% were white, and 25% were African American (Table 1) . Hypertension was the most common comorbidity affecting 95% of patients, followed by diabetes (52%), obesity (49%), heart disease (28%), and lung disease (19%). Twenty-eight percent of the patients had a prior or current history of smoking tobacco, whereas 15% had a history of cancer. Twenty-four patients Maintenance immunosuppression consisted of tacrolimus (91%), antimetabolite (mycophenolate) (77%), mTOR inhibitor (7.5%), and steroids (86%).

The most common symptoms on admission were fever and dyspnea (67%), followed by myalgia (53%) and diarrhea (38%) ( Table 2) . Table 1 ). Extracorporeal membrane oxygenation was used in 3 patients, none of whom survived.

There was no difference in mortality across the transplant centers.

Patients who died were older than survivors (66 vs 60 years old; P < .001), with 71% of patients over the age of 60 among nonsurvivors (Table 1 ). There was no significant difference in outcomes between recipients of organs from living or deceased donors or between patients with < 1 year since transplant compared with those with longer time TA B L E 1 Baseline demographics, comorbidities, and medications of hospitalized kidney transplant recipients with COVID-19 

The respiratory rate at admission was significantly higher in nonsurvivors compared with survivors ( (Table 2) , whereas ferritin, D-dimer, and C-reactive protein levels were not significantly different between groups.

In most cases, mycophenolate (MMF/MPA) or everolimus was reduced or discontinued (68%), whereas calcineurin inhibitor was discontinued in 32 patients (23%) ( Table 3 ). There was no significant association between immunosuppression withdrawal and mortality. Most patients received hydroxychloroquine (71%) and

antibiotics (74%), and a smaller subset of patients received tocilizumab (13%) or antivirals (14%) (Figure 1 ). There was no significant difference in mortality among different treatments of COVID-19 with the exception of a slightly greater use of antibiotics in nonsurvivors.

In univariable analysis, the odds of in-hospital death was higher in older patients and patients with higher respiratory rates, LDH, IL-6, and procalcitonin levels, whereas mortality risk was lower in patients with diarrhea or higher eGFR levels. These variables were used for the multivariable logistic regression model. In addition to age, we found that higher respiratory rate, lower eGFR, and higher IL-6 at admission were associated with increased odds of death (Table 4 ). Acute kidney injury is common in patients with COVID-19 due to multiple factors, including reduced renal perfusion, multiorgan failure, and cytokine storm. Although the range across centers is wide 3,4,13 and later reports showed a higher incidence of acute kidney injury, our data indicate that mortality and the burden of AKI Our multicenter study has several limitations. Individual centers had different approaches and access to medications for the treatment of COVID-19. Therefore, it is difficult to compare treatments, and our data reflect real-world use and outcomes of kidney transplant recipients with COVID-19. In addition, we have focused on a homogeneous cohort of hospitalized kidney transplant recipients, since criteria for diagnosis of COVID-19 in the ambulatory setting were variable and many patients did not have documented follow-up information from centers. Overall, this selection criteria limit the generalizability of our findings and prevent any conclusion about the overall mortality of all kidney transplant patients, only of hospitalized patients.

One other notable limitation of the study is the small sample and retrospective method, which may have resulted in false-positive results, or overestimation. We wish to emphasize the exploratory nature of the study, which was not driven by formal hypotheses but would instead hope that the findings presented here will inform larger studies going forward.

In conclusion, kidney transplant recipients should be closely monitored as they appear to have a high mortality and acute kidney injury rate. Investigation of the best strategy of immunosuppression adjustment on COVID-19 will be needed. Abbreviation: eGFR, estimated glomerular filtration rate.

The bold values indicates statistically significant values.

The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.

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The data that support the findings of this study are available from the corresponding author upon reasonable request.