key: cord-0776533-4mxoizbk
authors: AlOtaibi, Torki M.; Gheith, Osama A.; Abuelmagd, Mohammed M.; Adel, Mohammed; Alqallaf, Ahmed K.; Elserwy, Nabil A.; Shaker, Mohamed; Abbas, Ahmad M.; Nagib, Ayman M.; Nair, Prasad; Halim, Medhat A.; Mahmoud, Tarek; khaled, Mahmoud M.; Hammad, Mohamed A.; Fayyad, Zoheer A.; Atta, Ahmed F.; Mostafa, Ahmed Y.; Draz, Ahmed S.; Zakaria, Zakaria E.; Atea, Khaled A.; Aboatya, Hasaneen H.; Ameenn, Mohamed E.; Monem, Mohamed A.; Mahmoud, Amro M.
title: Better outcome of COVID‐19 positive kidney transplant recipients during the unremitting stage with optimized anticoagulation and immunosuppression
date: 2021-05-12
journal: Clin Transplant
DOI: 10.1111/ctr.14297
sha: f7625dcda03b95673ae8501f09a8eb5150c7e1bd
doc_id: 776533
cord_uid: 4mxoizbk

INTRODUCTION: COVID‐19 is an ongoing pandemic with high morbidity and mortality and with a reported high risk of severe disease in kidney transplant recipients (KTR). AIM: We aimed to report the largest number of COVID‐19‐positive cases in KTR in a single center and to discuss their demographics, management, and evolution. METHODS: We enrolled all the two thousand KTR followed up in our center in Kuwait and collected the data of all COVID‐19‐positive KTR (104) from the start of the outbreak till the end of July 2020 and have reported the clinical features, management details, and both patient and graft outcomes. RESULTS: Out of the one hundred and four cases reported, most of them were males aged 49.3 ± 14.7 years. Eighty‐two of them needed hospitalization, of which thirty‐one were managed in the intensive care unit (ICU). Main comorbidities among these patients were hypertension in 64.4%, diabetes in 51%, and ischemic heart disease in 20.2%. Management strategies included anticoagulation in 56.7%, withdrawal of antimetabolites in 54.8%, calcineurin inhibitor (CNI) withdrawal in 33.7%, the addition of antibiotics in 57.7%, Tocilizumab in 8.7%, and antivirals in 16.3%. During a follow‐up of 30 days, the reported number of acute kidney injury (AKI) was 28.7%, respiratory failure requiring oxygen therapy 46.2%, and overall mortality rate was 10.6% with hospital mortality of 13.4% including an ICU mortality rate of 35.5%. CONCLUSION: Better outcome of COVID‐19‐positive KTR in our cohort during this unremitting stage could be due to the younger age of patients and early optimized management of anticoagulation, modification of immunosuppression, and prompt treatment of secondary bacterial infections. Mild cases can successfully be managed at home without any change in immunosuppression.

Since the end of 2019, the novel coronavirus (severe acute respiratory syndrome coronavirus 2; SARS-CoV-2) has been transmitted from Wuhan, China to most of the countries. 1 The resulting disease, in immunocompromised individuals, particularly kidney transplant recipients. 2 It was noted that the viral burden and patient mortality rate were higher in infected transplant cases with past epidemics of coronavirus, 3 because of an impaired immunity, especially those with other medical comorbidities.

Transplant recipients, with compromised T-cell immunity, represent a group of patients who are more susceptible to develop COVID-19 because of their poor immunity that make them vulnerable to opportunistic infections. Till the end of August 2020, prevention is the main strategic plan, because of the lack of valid treatment or vaccine. Kidney transplantation programs were temporarily halted during this pandemic in many centers, particularly for highrisk elderly recipients with medical comorbidities. Strict compliance to handwashing, safe distancing, and regular virtual/telephonic evaluation of transplant patients were being carried out in many centers to reduce the prevalence and for the safe management of mild to moderate cases. The COVID-19 United Kingdom (UK) register was very resourceful in the management of difficult cases during these challenging times. 2, 4, 5 The first series of COVID-19-positive KTR (seven cases) came from south London, United Kingdom, 4 while the second series (twenty cases) reported from Brescia, Italy. 6 In the series from the United Kingdom, they reduced the immunosuppressive agents in combination with general supportive therapy without specific antiviral therapies.

Alberici et al 6 in their series, withdrew baseline immunosuppression in all patients. They added methylprednisolone in a dose of 16 mg per day, among nineteen out of twenty cases in addition to antiviral therapy and hydroxychloroquine (HCQ). They also used Tocilizumab (humanized anti-interleukin-6 receptor monoclonal antibody) in six of their patients along with dexamethasone to combat the uncontrolled cytokine release that developed in critically ill patients with acute respiratory distress syndrome (ARDS). They reported a mortality rate of 25% and AKI in 6 patients including one patient needing hemodialysis.

The prevalence of COVID-19-positive KTR during the period of pandemic is not well evaluated and the optimal management of these cases is not yet well-defined. In this setting, we undertook this study in our center, Organ Transplant Centre, Hamed Al Essa, Kuwait.

We aimed to study the COVID-19-positive kidney transplants and to evaluate their demographics, management, and outcome.

We have a single renal transplant center in Kuwait where nearly 2000 KTR are followed up. We collected the data from COVID-19positive kidney transplants that were diagnosed in all governmental hospitals from the first week of March 2020 till August 1, 2020. All COVID-19-positive adult KTR with a functioning allograft who presented to the causality and were either discharged or hospitalized were included. Clinical features, details of management, and both patient and graft outcomes were recorded. Patients' data were collected from the electronic database of both the parent transplant center and isolation hospitals where COVID −19 cases were managed. Patient characteristics were compared in two periods of time;

first period between March till the end of May 2020 and the second period during the next 2 months.

COVID-19 diagnosis was confirmed by a positive result on realtime polymerase chain reaction (RT-PCR) assay of nasopharyngeal swab specimens targeting the RNA-dependent RNA polymerase gene using amplification according to the manufacturer's recommendation. All electronic files on the database system were carefully revised for collection of patients' demographics, specifically the original kidney disease, type of dialysis, immediate graft function status, immunosuppressive agents, and other data especially the history of recent exposure, immunosuppression changes, clinical features suggesting COVID-19, and laboratory results with special stress on serum creatinine, liver function tests, treatment of secondary bacterial infections. Mild cases can successfully be managed at home without any change in immunosuppression.

antibiotic: antiviral, antiproliferative agent, COVID-19 in Kidney transplants, immunosuppressant, infection and infectious agents, kidney (allograft) function/dysfunction, kidney disease: infectious, viral procalcitonin (PCT), C-reactive protein (CRP), D-dimer, and complete blood count. AKI was considered and categorized according to Kidney Disease Improving Global Outcomes (KDIGO) criteria. AKI was staged for severity according to the following criteria: Stage 1 when creatinine was ranging between 1.5: <2 folds of baseline; stage 2 if the creatinine was ranging between 2: <3 folds, and stage 3 if creatinine was more than 3 folds of the baseline.

The study was approved by the ethical committee of the Ministry of Health of Kuwait.

The presence of a radiological abnormality was determined based on the descriptive documentation in medical charts of infected patients and when imaging scans were available, they were reviewed by the attending chest physician. A third reviewer opinion was taken if a major disagreement between the two initial reviewers happened.

The degree of severity of COVID-19 (non-severe vs. severe) at the time of hospital admission was defined using the American Thoracic Society (ATS) guidelines for community-acquired pneumonia. 7

Statistical analyses were performed using Statistical Package for the Social Sciences version 20.0 (SPSS). Qualitative data were presented as numbers and percentages, while quantitative variables were presented as means ± standard deviation and median. We used a T test to compare the means and standard deviations of the studied groups. Categorical variables were compared using the chi-squared test. p-values were considered significant if <.05.

In our study, 104 kidney transplants were confirmed as COVID-19 positive by PCR test and all of them were symptomatic. Eighty-two (78.8%) of these patients required hospital admission. Out of the eighty-two, thirty-one cases (37.8%) needed active care in the ICU and thirteen among these ICU patients required invasive ventilation.

Eleven of the 104 (10.6%) patients who were COVID-19 positive, died during this period.

The mean age of COVID-19-positive cases was 49.3 ± 14.7 years.

(Patient demographics are summarized in Table 1 

The characteristics of the study population are listed in Table 1 (Table 1) .

Allograft function was stable in 88 (84.6%) patients. AKI was reported in thirty patients: six with stage 3, seven with stage 2, and seventeen with stage 1. (Table 1 ) Six patients developed oligo-anuria needing renal replacement therapy using continuous venovenous hemodiafiltration (CVVHDF) due to hyperkalemia (2 cases), hypervolemia (2 cases) and both conditions in the remaining 2 cases (Table 3 ).

At the time of hospital admission, leukopenia (less than 4000 cells/microliter) was confirmed in 18.3% of patients while the mean levels of CRP, D-dimer, and ferritin were reported as 119 ± 159, 1397 ± 3919, and 648 ± 543, respectively ( Table 2) .

Though more than 53% of patients did not need oxygen support, non-invasive and invasive ventilation was needed in 48 cases in the ICU (47.2% of cases). Only one patient was managed by ECMO (Tables 1, 3) .

From Table 3 , it can be noted that majority of the hospitalized patients were older than 50 years, had ischemic heart disease, and presented with fever and dyspnea with bilateral radiologic findings (p < .05). Most ICU admissions were in COVID-19 isolation hospitals and they had all COVID-19 risk factors (p < .05) and

presented with cough, dyspnea, and bilateral radiological findings compatible with COVID-19 (p < .05). AKI was also more prevalent in ICU patients and they had significantly poorer patient and graft outcomes (p < .05).

At the end of the follow-up, ninety-three patients were alive (88 with functioning grafts, 4 with failed and 12 with impaired grafts, 

Baseline immunosuppressive (IS) regimens and their modifications are summarized at the end of Table 1 , Figure 2 . At the time of COVID-19 presentation, twenty-nine cases were maintained on a cyclosporine-based regimen while sixty-two cases were maintained on Tacrolimus-based therapy. As can be seen in 

The 

Among the hospitalized cases, low molecular weight heparin was started in 59 cases (56.7%) and an additional antibacterial (mono-or combined therapy) was given in 60 (57.7%) cases and this was including piperacillin/tazobactam, azithromycin, ceftriaxone, levofloxacin, cefepime, and vancomycin. During the period of lockdown, our transplant program was temporarily withheld and patients were being evaluated, as many transplant centers, did via mobile applications. Patients with more severe manifestations were reviewed in the COVID-19 triage area of our hospital (with full use of patient protective equipment) or COVID-19

isolation hospitals, to minimize the risk of infecting other transplant patients. This policy was adopted by many transplant centers. 8 To the best of our knowledge, this study included a significantly high number of COVID-19-positive KTR with their data collected from their initial contact with the healthcare provider and from the tertiary COVID-19 general hospitals where they were managed.

Most of these patients had their transplant more than a year ago and so the impact of induction therapy has been nullified. Only ten patients out of 104 (9.6%) had their transplant less than a year ago and out of these, two died with impaired graft function and eight were discharged with functioning grafts.

The risk factors for a bad outcome that are reported in the general population included advanced age, male gender, and preexisting comorbidities especially hypertension, diabetes, and ischemic heart disease. [14] [15] [16] In our cohort, all hospitalized patients had more comorbidities, unambiguously cardiovascular (hypertension and ischemic heart disease), and more severe symptoms at the time of admission.

These patients also had elevated levels of ferritin, D-dimer, PCT, and CRP, which are markers of severe disease and poor prognosis as has been reported in other studies. 17 Most patients had radiological features suggestive of viral bronchopneumonia on an X-ray or HRCT chest which was considered as moderate to severe illness and despite those features, 53.5% did not need oxygen therapy. 18 Eighty-two (78.8%) of our patients were hospitalized, with thirty-one (29.8%) cases needed admission to the ICU.

The mortality rate reported in our cohort is lower than that reported In our cohort, we observed patient survival was significantly poorer among those who received higher doses of steroid together with discontinuation of either antiproliferative and/or CNI (11 out of 33 cases). This could probably be explained by the fact that these were patients with more severe disease and they were also associated with poor graft outcome. (Table 4 ). On the contrary, all patients who continued their maintenance immunosuppression recovered fully (47 cases, Table 4 ). This finding was matched with that reported by Lubetzky et al as well, as 13 of his cohort of 14 hospitalized F I G U R E 2 Showed our adopted management protocol of COVID-19-positive kidney transplant recipients patients who continued on MMF and were successfully discharged from the hospital. 8 Moreover, one of the gravest complications of COVID-19 is uncontrolled cytokine release and its consequences. It was reported that CNI may be potentially helpful in their ability to diminish uncontrolled cytokine release through inhibition of nuclear localization of the nuclear factor of activated T cells. 31 This might support the hypothesis that immune-reduction rather than cessation could be beneficial to inhibit cytokine and might explain the relatively lower circulating cytokine levels compared with patients having bacterial sepsis. 32

Most COVID-19 related mortality is linked with ARDS which is induced by uncontrolled cytokine release. 33, 34 Therefore, some form of immunosuppression may be needed in this situation for blockade of Interleukin-6 (IL-6) and interleukin-1 (IL-1). There are studies underway using drugs for blockade of IL-6 and IL-1 in the management of COVID-19.

Majority of our hospitalized patients did not receive hydroxychloroquine (HCQ) because of the lack of sufficient scientific data regarding its efficiency, when prescribed alone or with azithromycin either in mild to moderate cases 35, 36 or even as pre-exposure prophylaxis. 37 Moreover, the possible cardiac toxicity of prolonged QT interval and tachyarrhythmias when HCQ is combined with azithromycin has been reported. 38 in their hospitalized transplants. The lower prevalence of AKI in our cohort could be explained by the relatively lower rate of uncontrolled cytokine release and less nephrotoxic agents especially CNI. It is worth mentioning that Tacrolimus bioavailability is increased due to short intestinal transit time with diarrhea in cases of COVID-19. 44 Moreover, an earlier start of anticoagulation might explain the lower rate of AKI in our cohort as hypercoagulation and thrombotic micro-angiopathy was mentioned as one of the multifactorial mechanisms of AKI in such patients. 45, 46 The increased number of infected patients during the last two months of the study could be explained by the lack of strict precautions that were followed during the lockdown period of the initial four months of the study.

This includes the retrospective nature of the study, short-term follow-up, and lack of graft biopsies for cases of AKI.

During this unremitting COVID-19 pandemic, strict preventive precautions should continue. A coordinated and multidisciplinary approach is ideal for managing COVID-19-positive kidney transplants. Patients with mild symptoms-especially in resources restricted regions can be successfully managed at home with telecommunication for symptom progression with tailoring of immunosuppressive agents to prevent uncontrolled cytokine release.

For hospitalized patients, relatively younger age, sensible reduction in immunosuppressive drugs (depending on clinical progression), early anticoagulation, and prompt therapy of co-bacterial infections might be the reasons for our favorable outcome.

However, AKI was observed in a considerable percentage of patients that needed hospitalization and the worst prognostic factor was the need for ventilation.

We would like to acknowledge staff members of Hamed Al-Essa organ transplant center and jabber hospital, who suffered a lot during the COVID-19 pandemic. This paper is wholehearted to them, as their dynamic share of knowledge about COVID-19 made it possible.

Authors have no conflict of interest to disclose.

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

Osama A. Gheith https://orcid.org/0000-0002-7324-0211

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