key: cord-0851206-p80ko9gq
authors: Imam, Ashraf; Abukhalaf, Sadi A.; Imam, Riham; Abu-Gazala, Samir; Merhav, Hadar; Khalaileh, Abed
title: Kidney Transplantation in the Times of COVID-19 – A Literature Review
date: 2020-07-24
journal: Ann Transplant
DOI: 10.12659/aot.925755
sha: 6da1b4c2e94c64698e9709fe758d2b7f91ce9f38
doc_id: 851206
cord_uid: p80ko9gq

Kidney transplantation at the time of the COVID-19 pandemic is challenging. Modifying the immunosuppression protocols is controversial and not evidence based. In this study, we aim to review the published literature of kidney transplant recipients who encountered COVID-19. A literature review was performed using PubMed, ScienceDirect, and World Health Organization databases to identify relevant English-language articles published up to May 7, 2020. There were 24 articles that reported 129 kidney transplant recipients who encountered COVID-19. The age mean was 54.2 years with 73.7% as males. The most commonly reported presentations in order were fever (82.3%), cough (58%), shortness of breath (33.2%), and fatigue (30.7%). Acute kidney injury was observed in 34.1% of patients. Kidney transplant patients encountered COVID-19 were maintained on tacrolimus (Tac, 92%), mycophenolate mofetil (MMF, 78.8%), and prednisone (Pred, 77%) and were manage by holding MMF in 79.1% of patients and holding Tac in 34.4% of patients. In all, 20% of patients needed Intensive Care Unit (ICU) admission and 24.6% of patients required mechanical ventilation. In all, 18.8% of patients had died compared to the reported general population COVID-19 mortality of 3.4%. The clinical presentation of COVID-19 in kidney transplant recipients may be different from the general population with a higher rate of severe disease, complications including renal failure, and mortality.

Coronavirus disease 2019 is caused by the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV2) [1] . The disease was initially confirmed in China and then rapidly spread worldwide with more than 2 million infected individuals and over 200 000 deaths worldwide [2] . This disease is especially fatal in elderly patients (patients older than 70 years) with comorbidities [3] . Most published data regarding COVID-19 and organ transplant recipients is nonspecific and lacks quality evidence. Data about demographics, characteristics, and clinical presentations of COVID-19 in kidney transplant recipients is scarce [4] . In this study, we aimed to review the published literature regarding kidney transplant patients who encountered COVID-19.

A systematic literature review was performed using PubMed and ScienceDirect databases to identify relevant English-language articles published through May 6, 2020. Search terms included COVID-19, coronavirus, severe acute respiratory syndrome coronavirus 2, 2019-nCoV, SARS-CoV-2, SARS-CoV, MERS-CoV and transplantation. All article types were included: case reports, case series, commentaries, and review articles. A search in the database of the COVID-19 global research on coronavirus disease section of the World Health Organization (WHO) website through May 6, 2020 was performed using the following criteria: transplantation without any additional limits or filters [5] . Additional articles were retrieved by screening the reference lists of the included studies. The search strategy was approved and reviewed by all authors.

The authors independently reviewed the titles and abstracts for inclusion. Figure 1 displays the flow diagram for this systematic review, based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2009 [6] . Databases were screened, filtered, and assessed for eligibility. Cases of COVID-19 in kidney transplant patients were included in this study. Articles with unrelated topics and/or with missed information were excluded.

The National Institutes of Health Quality Assessment Tool for Case Series Studies was used to qualify the reviewed articles [7] . Table 1 shows the results of the 2 reviewers who independently rated the quality of the included studies.

Data was independently extracted from reports by 2 reviewers. All reported patients' demographic and clinical characteristics (country, age, sex, time from transplant, donor type, comorbidities, clinical presentation and maximum body temperature, initial complete blood count (CBC), C-reactive protein (CRP), baseline creatinine (Cr), blood urea nitrogen (BUN), renal involvement, baseline immunosuppressant medications, need for intensive care unit (ICU) and mechanical ventilation (MV), duration of illness and outcomes) were extracted, collected and analyzed. Due to the lack of sufficient data, a meta-analysis to assess the association of various patients' findings with demographic data, disease and patient characteristics, or outcomes was not performed. The principal summary measures used were the median, mean, standard deviation, and incidence.

A total of 493 articles were retrieved using the search strategy. After duplication removal, 378 articles were screened; 331 articles were excluded due to unrelated content. The remaining 47 articles were assessed for eligibility through full-text screening. There were 15 articles excluded due to unrelated content or lack of relevant information. There were 32 articles included but only 21 articles reported kidney transplant recipients encountered COVID-19 ( Figure 1 ). For quality assessment, we used the NIH Quality Assessment Tool for Case Series Studies [7] . Five case series and 16 case reports included 58 kidney transplant patients encountered COVID-19. Patients' characteristics and demographics were included in Tables 2-4 . Table 3 .

The most frequently reported clinical presentation was fever; it was reported in 49 patients (84.5%) with a mean maximum temperature of 38.47°C (±0.79°C). Other reported clinical symptoms were cough (70%), shortness of breath (SOB) (56.9%), flu-like symptoms including myalgia and fatigue (60%), gastrointestinal symptoms including vomiting, diarrhea, nausea, abdominal pain/bloating and hyporexia/anorexia (44.8%), chills (17.2%), and chest pain/tightness/discomfort (6.9%). Less frequently reported symptoms included headache, dizziness, sore throat, rhinorrhea, nasal congestion, and stuffiness, coryza, dehydration, conjunctivitis, hematuria, and oliguria. These variables are presented in the Table 3 .

The initial white blood cell count median was 6×10 9 (±3.4×10 9 ). The initial median lymphocyte cell count was 0.6×10 9 (±0.72×10 9 ). Initial leukopenia and lymphopenia were reported in 22.8% and 63%, respectively. However, lymphopenia was eventually developed in 79% of patients. Median of the initial CRP was 49 mg/L (±92.4 mg/L) and high CRP (>5 mg/dL) levels were noted in 97.2% of cases. Median of the baseline serum Cr was 1.65 mg/dL (±0.96 mg/dL) and 85% of patients had baseline serum Cr >1.2 mg/dL. Median initial (post infection) serum Cr was 1.9 mg/dL (±1.7 mg/dL) and acute kidney injury (AKI) was observed in 28.2% of patients. High D-dimer (>500 µg/L), ALT (>50 U/L), AST (>54 U/L), and LDH (>225 U/L) levels were observed in 72.7%, 44%, 15%, and 69.2%, respectively. These variables are presented in the Table 3 .

Patients were treated with different immunosuppressive regimens though the most frequently reported regimen included tacrolimus (Tac), mycophenolate mofetil (MMF), and prednisone (Pred) which was reported in 33 patients (56.9%).

Pred was prescribed in 81% of patients and discontinued in 14.8%, increased in 4.2% and not changed in 80.8%. MMF was prescribed in 79.3% of patients and discontinued in 72%, reduced in 4.3%, and not changed in 15.2%. Tac was prescribed in 82.7% of patients and discontinued in 47.9%, reduced in 20.8%, and not changed in 25.8%. Other baseline immunosuppression medications were azathioprine, everolimus, ciclosporin, sirolimus, and mizoribine. These medications were held in some patients and not changed in others; 13.8% of patients recovered with no change in immunosuppression medications. These variables are presented in the Table 4 . by increasing the dose of prednisone. These variables are presented in the Table 4 . 

The mean age was 66.2 years with 55.5% of patients older than 65 years; 55.5% of patients were male and the mean of the transplant age was 9.7 years. Hypertension, diabetes mellitus, and COPD were reported in 88.8%, 33.3%, and 100% of patients, respectively. In addition, 66.6% of patients had lymphopenia and 66.6% had high CRP serum levels. Acute kidney injury (AKI) was reported in 44.4% of patients (Table 5) . 

Three studies reported 36, 20, and 15 patients, respectively. These studies reported results without demographics and characteristics for each patient and thus were not included in our tabulated results. However, these 3 studies were used to draw pooled measures for all reported kidney transplant patients who encountered COVID-19, found in the literature. The total number of kidney transplant patients who encountered COVID-19 reported in the literature was 129 cases. The age mean was 54.2 years with 73.7% of the patients were males. The transplant age mean was 8.2 years with 65.4% of the transplants from a deceased source. Hypertension, diabetes mellitus, and coronary artery disease were reported in 82.6%, 40%, and 14% of cases, respectively. The most commonly reported presentations in order were fever (82.3%), cough (58%), SOB (33.2%), fatigue (30.7%), diarrhea (19.7%), myalgia (17.3%), sore throat (7.6%), and vomiting (6.9%) ( Table 6 ).

The initial white blood cell count mean was 5.37×10 9 . The initial mean lymphocyte cell count was 0.77×10 9 . Leukopenia and lymphopenia were reported in 21.9% and 79% of patients, respectively. Mean initial CRP was 52.4 mg/L and high CRP (>5 mg/dL) levels were noted in 71.6% of cases. Mean initial (post infection) serum Cr was 1.85 mg/dL and AKI was observed in 34.1% of patients. High D-dimer (>500 µg/L) and lactate dehydrogenase (LDH, >225 U/L) levels were observed in 64.8% and 52.6%, respectively. Kidney transplant patients encountered COVID-19 were maintained on Tac (92%), MMF (78.8%), Pred (77%), and azathioprine (5.2%) and were manage by holding MMF in 79.1% of patients and holding Tac in 34.4% of patients. These patients received treatments targeted for COVID-19 which included hydroxychloroquine (77.6%), lopinavir/ritonavir (49.8%), antibiotics (48%), azithromycin (40.5%), and tocilizumab (11.8%). Overall, 20% of patients needed ICU admission, 24.6% of patients required MV, 42% of patients recovered and were discharged, 41.3% of patients were alive and hospitalized at the time of the study publication, and 18.8% of patients had died (Tables 6, 7 ).

Fever in COVID-19 has been reported in 99% of patients [18, 19] . Our study has found that 15% of the kidney transplant patients had no fever on presentation or during their hospitalization. On the other hand, cough, shortness of breath, myalgia, headache, sore throat, and gastrointestinal symptoms were more common than the typical COVID-19 presentation [18] [19] [20] [21] .

Additionally, this review found that there were several unreported symptoms that appeared in the COVID-19 positive kidney transplant patients, like chest tightness and pain, coryza, dehydration, conjunctivitis, dizziness, and weight loss [20] . Interestingly, the previously unreported chest tightness and pain symptoms in other cohorts had an incidence of 7% in this cohort.

COVID-19 causes of pneumonia can be severe enough to be lethal, especially in patients with advanced age or underlying medical comorbidities [22] . Those comorbidities include cardiovascular disease, diabetes mellitus, hypertension, chronic lung disease, cancer, chronic kidney disease, and obesity (body mass index ³30 kg/m 2 ) [3, 22] . Kidney transplant patients infected with COVID-19 are a fragile and high-risk group due to immunosuppressant medications (ISMs), kidney disease, and common comorbidities. In this review, 81% of patients had comorbidities, with diabetes mellitus and hypertension as the most common reported comorbidities. This fact exposes those patients to a more severe COVID-19 infection, not to mention the additional unclear risk of the immunosuppression. Kidney transplant recipients and candidates are as a rule in a highrisk group due to the high incidence and prevalence of hypertension, diabetes, obesity, and advanced age in this group.

It was previously reported that a progressive decline in lymphocyte count was observed in non-survivors compared to more stable levels in survivors [18] . In the present study, 66.6% of patients who died had lymphopenia. Given the fact that ISMs can induce lymphopenia, many kidney transplant patients can have a baseline lymphopenia that might further deteriorate and worsen the prognosis [8] .

AKI, proteinuria, and hematuria have all been reported in COVID-19 patients. AKI has been reported to have occurred in 25% to 29% of critically ill COVID-19 patients in Wuhan, China [23, 24] . The incidence of AKI among patients who are less severely ill is unknown. In our cohort, AKI was reported in 28.2% of patients. However, the pooled AKI prevalence was 34.1% (see Table 6 ). This may indicate that kidney transplant patients infected with COVID-19 are more likely to have AKI than other cohorts. AKI has been associated with worse outcomes [25] cohort, mild disease was only reported in 43% of patients while severe disease that presents with SOB or hypoxia was reported in 57% of patients.

The WHO reported that recovery time appears to be around 2 weeks for mild infections and 3 to 6 weeks for severe disease [27] . In this report, it appears that 62% of patients recovered clinically from the COVID-19 with a median duration of illness of 17.5 days (range, 7 to 48 days). Rates of ICU admission were reported to range between 5% to 12% while the rate of MV was 2.3% in the general population [28, 29] . In our cohort, 19% of patients were admitted to the ICU and 22.4% of patients required MV.

The most recently reported mortality rate of COVID-19 was 3.77% [30] . The mortality rate of kidney transplant patients infected with COVID-19 in this cohort was 15.5% (9 out of 58 patients) and the pooled mean was 18.8%. Despite the small number of patients included in the present study, this high mortality rate indicates that COVID-19 in kidney transplant patients may portend an ominous outcome. We found that 11.1% of the 1-year transplant age patients had died while 16.3% mortality was found for patients with transplant age more than 1 year.

It has been reported that 81% of COVID-19 patients present with mild disease and can be managed at home, while severe and critical COVID-19 disease should be managed with prompt hospitalization while ensuring appropriate infection control and supportive care [23, 31, 32] . The hospitalized patients should be managed with empiric treatment for bacterial pneumonia in selected patients, prevention of venous thromboembolism, and avoiding nebulized medications. The WHO and CDC recommend against systemic glucocorticoids in COVID-19 patients unless there are other indications [31, 32] . To date, all suggested medications are under investigation with no proven efficacy against COVID-19. These medications include remdesivir, hydroxychloroquine/chloroquine, azithromycin and hydroxychloroquine, convalescent plasma, tocilizumab, favipiravir, interferon beta, and lopinavir/ritonavir. A registry of international clinical trial can be found at https://www.clinicaltrials.

gov/ct2/results?cond=covid19&term=&cntry=&state=&city=& dist. Most of our cohort had been hospitalized and could not be managed at home due to the severity of the disease. They had been managed with antibiotics (41.3%), hydroxychloroquine (43.1%), intravenous methylprednisolone (32.7%), intravenous immunoglobulin (25.8%), lopinavir/ritonavir (20.6%), unspecified antivirals (17.2%), azithromycin (15.5%), oseltamivir (13.8%), interferon a,b (5.2%), tocilizumab (3.4%), and remdesivir (1.7%).

The effect of immunosuppression on the progression of COVID-19 is not clear yet. There are 2 aspects that cannot be ignored when dealing with immunosuppression and COVID-19. Firstly, it was proven that COVID-19 patients have a high prevalence of lymphopenia [33] but it is not clear yet whether lymphopenia is a risk factor for COVID-19 or a result of it. Secondly, it is thought that the severity of COVID-19 may be the result of a hyperinflammatory response (cytokine storm). Thus, many have questioned the role of immunomodulation in the treatment of severe cases [34, 35] .

Interestingly, D'Antiga from Italy recently published a study that concluded that immunocompromised patients do not have an increased risk of developing severe pulmonary disease compared to the general population [36] .

Kidney transplant patients may present with atypical clinical picture of the COVID-19. Fever may be absent while other atypical symptoms may prevail. Therefore, a high index of suspicion for COVID-19 and perhaps even surveillance in this population may help in early diagnosis and prevention of further transmission. The role of immunosuppression therapy should be assessed in every case individually.

None.

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