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      SARS-CoV-2 Infection Results in Serious Kidney Impairment: More Studies Need to Be Explored

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      American Journal of Nephrology
      S. Karger AG

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          Abstract

          Dear Editor, We appreciate the letters by Dr. Bhaskar et al. [1] and by Dr. Silver et al. [2]. In their letters, they put forward some views and comments on our article “Coronavirus Disease 19 Infection Does Not Result in Acute Kidney Injury: An Analysis of 116 Hospitalized Patients from Wuhan, China” [3]. All of the issues raised by them are very important and deserve our attention and considerations. Here, we would like to respond to their comments in the letters and explain their questions about the observations in our paper. We hope that our responses could relieve them of some concerns. As regards Dr. Bhaskar et al.'s concern about the roles of ACE2 expression in SARS-CoV-2 infection, a recent study shows that the cells with ACE2 expression may act as target cells and be susceptible to SARS-CoV-2 infection, such as type II alveolar cells in the lung [4]. It should be noted that the ACE2 protein has been proved to have an abundant expression in many kinds of cells, including renal tubular epithelial cells. Therefore, it is reasonable to speculate that SARS-CoV-2 may also invade kidney and lead to AKI. However, the information regarding the pathological findings in COVID-19 is limited at present. The reports showed that there were main histological changes in the lung [5, 6]. Until now, there are no data and evidence showing that SARS-CoV-2 infection might directly impair the kidney, although SARS-CoV-2 RNA could be detected from urine, including our results [3]. Therefore, in addition to the lung, whether the kidney is the main target organ of SARS-CoV-2 and it causes an obvious AKI need more pathological and virological evidence in the future study. Moreover, data on ACE inhibitor application in COVID-19 are important in this setting and should also be investigated. As regards Dr. Bhaskar et al.'s concern about mortality in our study, we included 116 patients with COVID-19 hospitalized in the Department of Infectious Diseases. Eleven (11/116, 9.5%) patients were with acute respiratory distress syndrome (ARDS) and were transferred to ICU. Seven out of 11 ARDS patients transferred to ICU died of respiratory failure. As a result, the overall mortality rate of COVID-19 was 6.03% (7/116), while the mortality rate of ARDS patients with COVID-19 in ICU was 63.6% (7/11). There is indeed a high mortality, which is in agreement with the results of the study by Wu et al. [7]. As regards Dr. Silver et al.'s concern about the incidence of AKI in patients with COVID-19, our explanations and answers are as follows. Our department started to treat patients with COVID-19 from the middle of January 2020. Previously, these patients were consultant in “fever clinic,” which serves as an outpatient department, and were diagnosed as “unknown origin viral pneumonia” for admission. They were confirmed the diagnosis as COVID-19 by the SARS-CoV-2 RNA test immediately, when PCR detection was available. In that time, our wards were specialized for isolation and treatment of these patients. Thirty out of 116 cases with other diseases already hospitalized at the time of their COVID-19 were diagnosed. The others were newly admitted from “fever clinic.” All hospitalized patients in our wards were at the acute phase of their illness. The patients clinical categories and comorbidities are presented in table 1 of our paper. The judgment of patients' condition and clinical type is mainly based on the degree of hypoxemia and lung damage [8]. In our paper, AKI was identified according to Kidney Disease: Improving Global Outcomes (KDIGO) [9]. However, few patients without CKD could accurately provide the baseline levels of SCr. When baseline SCr was not available, SCrGFR-75 as surrogate for the baseline SCr was used to diagnose AKI [10]. Renal function and urine were tested weekly in all patients during the treatment of COVID-19. Although the weekly test may not have been sufficiently frequent in certain instances for finding AKI, the high frequency of examination is useful, especially in critical patients. In this study, 5 patients with ESKD received regular dialysis. The serum creatinine, blood urea, electrolytes, and urine analysis were used to evaluate whether kidney deterioration occurs in them. The symptoms, physical examination results, hemodynamic stability (e.g., blood pressure) were closely monitored as well. Although AKI is currently reported in critical cases of COVID-19, especially in dead cases as high as 23–32% [11, 12], it may be related to severe hypoxemia and/or multiple organ dysfunction syndrome (MODS) induced by inflammatory storm or to high comorbidities. Whether this renal injury is directly caused by SARS-CoV-2 infection is still unclear. In our paper, we did not find a significant AKI in these 11 ARDS cases, including 7 dead patients with ARDS. The critical patients in our study were in small number. Therefore, the differences on kidney impairment from available studies in COVID-19 may associate with the severity of illness. Many early studies suggested a lower incidence (3–9%) of AKI in those with COVID-19 infection [13, 14, 15]. As an early report, our study showed clinical data of 116 hospitalized COVID-19 patients analyzed over 4 weeks for correlation with renal injury. Approximately 10.8% of patients with no prior kidney disease showed elevations in blood urea or creatinine, and 7.2% of patients with no prior kidney disease showed albuminuria. All these patients did not meet the diagnostic criteria of AKI. From these results, we concluded that AKI was uncommon in general population with COVID-19. Based on the study from SARS-CoV infection in SARS patients in 2003 [16], the data showed that AKI was uncommon, but the mortality was formidably high (91.7%, 33 of 36 cases). Our results were similar and consistent with the presentation of renal injury in SARS. Moreover, in the present study, we also found that unlike a high mortality in SARS complicated with renal injury, none of 5 patients with CKD died from SARS-CoV-2 infection. Actually, our study showed that a mild renal injury was present rather than AKI in general population with COVID-19. We also suggested that regular monitoring of renal function in COVID-19 patients is necessary, especially in patients with elevated plasma creatinine levels. In the event of signs of AKI, potential interventions, including CRRT, should be used as early as possible. Finally, our study is a preliminary and retrospective analysis, which had several limitations. Whether SARS-CoV-2 infection results in serious kidney impairment remains to be explored further. It will be crucial to comprehensively characterize larger datasets of COVID-19 patients across hospitals (meta-analyses) to demonstrate if the kidney function is actively impaired due to the viral infection and SARS-CoV-2 could easily lead to kidney damage and if renal diseases are a major high risk factor for aggravating COVID-19 consequences. Disclosure Statement We declare no competing interests.

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          Most cited references17

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          Clinical Characteristics of Coronavirus Disease 2019 in China

          Abstract Background Since December 2019, when coronavirus disease 2019 (Covid-19) emerged in Wuhan city and rapidly spread throughout China, data have been needed on the clinical characteristics of the affected patients. Methods We extracted data regarding 1099 patients with laboratory-confirmed Covid-19 from 552 hospitals in 30 provinces, autonomous regions, and municipalities in mainland China through January 29, 2020. The primary composite end point was admission to an intensive care unit (ICU), the use of mechanical ventilation, or death. Results The median age of the patients was 47 years; 41.9% of the patients were female. The primary composite end point occurred in 67 patients (6.1%), including 5.0% who were admitted to the ICU, 2.3% who underwent invasive mechanical ventilation, and 1.4% who died. Only 1.9% of the patients had a history of direct contact with wildlife. Among nonresidents of Wuhan, 72.3% had contact with residents of Wuhan, including 31.3% who had visited the city. The most common symptoms were fever (43.8% on admission and 88.7% during hospitalization) and cough (67.8%). Diarrhea was uncommon (3.8%). The median incubation period was 4 days (interquartile range, 2 to 7). On admission, ground-glass opacity was the most common radiologic finding on chest computed tomography (CT) (56.4%). No radiographic or CT abnormality was found in 157 of 877 patients (17.9%) with nonsevere disease and in 5 of 173 patients (2.9%) with severe disease. Lymphocytopenia was present in 83.2% of the patients on admission. Conclusions During the first 2 months of the current outbreak, Covid-19 spread rapidly throughout China and caused varying degrees of illness. Patients often presented without fever, and many did not have abnormal radiologic findings. (Funded by the National Health Commission of China and others.)
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            Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study

            Summary Background In December, 2019, a pneumonia associated with the 2019 novel coronavirus (2019-nCoV) emerged in Wuhan, China. We aimed to further clarify the epidemiological and clinical characteristics of 2019-nCoV pneumonia. Methods In this retrospective, single-centre study, we included all confirmed cases of 2019-nCoV in Wuhan Jinyintan Hospital from Jan 1 to Jan 20, 2020. Cases were confirmed by real-time RT-PCR and were analysed for epidemiological, demographic, clinical, and radiological features and laboratory data. Outcomes were followed up until Jan 25, 2020. Findings Of the 99 patients with 2019-nCoV pneumonia, 49 (49%) had a history of exposure to the Huanan seafood market. The average age of the patients was 55·5 years (SD 13·1), including 67 men and 32 women. 2019-nCoV was detected in all patients by real-time RT-PCR. 50 (51%) patients had chronic diseases. Patients had clinical manifestations of fever (82 [83%] patients), cough (81 [82%] patients), shortness of breath (31 [31%] patients), muscle ache (11 [11%] patients), confusion (nine [9%] patients), headache (eight [8%] patients), sore throat (five [5%] patients), rhinorrhoea (four [4%] patients), chest pain (two [2%] patients), diarrhoea (two [2%] patients), and nausea and vomiting (one [1%] patient). According to imaging examination, 74 (75%) patients showed bilateral pneumonia, 14 (14%) patients showed multiple mottling and ground-glass opacity, and one (1%) patient had pneumothorax. 17 (17%) patients developed acute respiratory distress syndrome and, among them, 11 (11%) patients worsened in a short period of time and died of multiple organ failure. Interpretation The 2019-nCoV infection was of clustering onset, is more likely to affect older males with comorbidities, and can result in severe and even fatal respiratory diseases such as acute respiratory distress syndrome. In general, characteristics of patients who died were in line with the MuLBSTA score, an early warning model for predicting mortality in viral pneumonia. Further investigation is needed to explore the applicability of the MuLBSTA score in predicting the risk of mortality in 2019-nCoV infection. Funding National Key R&D Program of China.
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              Pathological findings of COVID-19 associated with acute respiratory distress syndrome

              Since late December, 2019, an outbreak of a novel coronavirus disease (COVID-19; previously known as 2019-nCoV)1, 2 was reported in Wuhan, China, 2 which has subsequently affected 26 countries worldwide. In general, COVID-19 is an acute resolved disease but it can also be deadly, with a 2% case fatality rate. Severe disease onset might result in death due to massive alveolar damage and progressive respiratory failure.2, 3 As of Feb 15, about 66 580 cases have been confirmed and over 1524 deaths. However, no pathology has been reported due to barely accessible autopsy or biopsy.2, 3 Here, we investigated the pathological characteristics of a patient who died from severe infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by postmortem biopsies. This study is in accordance with regulations issued by the National Health Commission of China and the Helsinki Declaration. Our findings will facilitate understanding of the pathogenesis of COVID-19 and improve clinical strategies against the disease. A 50-year-old man was admitted to a fever clinic on Jan 21, 2020, with symptoms of fever, chills, cough, fatigue and shortness of breath. He reported a travel history to Wuhan Jan 8–12, and that he had initial symptoms of mild chills and dry cough on Jan 14 (day 1 of illness) but did not see a doctor and kept working until Jan 21 (figure 1 ). Chest x-ray showed multiple patchy shadows in both lungs (appendix p 2), and a throat swab sample was taken. On Jan 22 (day 9 of illness), the Beijing Centers for Disease Control (CDC) confirmed by reverse real-time PCR assay that the patient had COVID-19. Figure 1 Timeline of disease course according to days from initial presentation of illness and days from hospital admission, from Jan 8–27, 2020 SARS-CoV-2=severe acute respiratory syndrome coronavirus 2. He was immediately admitted to the isolation ward and received supplemental oxygen through a face mask. He was given interferon alfa-2b (5 million units twice daily, atomisation inhalation) and lopinavir plus ritonavir (500 mg twice daily, orally) as antiviral therapy, and moxifloxacin (0·4 g once daily, intravenously) to prevent secondary infection. Given the serious shortness of breath and hypoxaemia, methylprednisolone (80 mg twice daily, intravenously) was administered to attenuate lung inflammation. Laboratory tests results are listed in the appendix (p 4). After receiving medication, his body temperature reduced from 39·0 to 36·4 °C. However, his cough, dyspnoea, and fatigue did not improve. On day 12 of illness, after initial presentation, chest x-ray showed progressive infiltrate and diffuse gridding shadow in both lungs. He refused ventilator support in the intensive care unit repeatedly because he suffered from claustrophobia; therefore, he received high-flow nasal cannula (HFNC) oxygen therapy (60% concentration, flow rate 40 L/min). On day 13 of illness, the patient's symptoms had still not improved, but oxygen saturation remained above 95%. In the afternoon of day 14 of illness, his hypoxaemia and shortness of breath worsened. Despite receiving HFNC oxygen therapy (100% concentration, flow rate 40 L/min), oxygen saturation values decreased to 60%, and the patient had sudden cardiac arrest. He was immediately given invasive ventilation, chest compression, and adrenaline injection. Unfortunately, the rescue was not successful, and he died at 18:31 (Beijing time). Biopsy samples were taken from lung, liver, and heart tissue of the patient. Histological examination showed bilateral diffuse alveolar damage with cellular fibromyxoid exudates (figure 2A, B ). The right lung showed evident desquamation of pneumocytes and hyaline membrane formation, indicating acute respiratory distress syndrome (ARDS; figure 2A). The left lung tissue displayed pulmonary oedema with hyaline membrane formation, suggestive of early-phase ARDS (figure 2B). Interstitial mononuclear inflammatory infiltrates, dominated by lymphocytes, were seen in both lungs. Multinucleated syncytial cells with atypical enlarged pneumocytes characterised by large nuclei, amphophilic granular cytoplasm, and prominent nucleoli were identified in the intra-alveolar spaces, showing viral cytopathic-like changes. No obvious intranuclear or intracytoplasmic viral inclusions were identified. Figure 2 Pathological manifestations of right (A) and left (B) lung tissue, liver tissue (C), and heart tissue (D) in a patient with severe pneumonia caused by SARS-CoV-2 SARS-CoV-2=severe acute respiratory syndrome coronavirus 2. The pathological features of COVID-19 greatly resemble those seen in SARS and Middle Eastern respiratory syndrome (MERS) coronavirus infection.4, 5 In addition, the liver biopsy specimens of the patient with COVID-19 showed moderate microvesicular steatosis and mild lobular and portal activity (figure 2C), indicating the injury could have been caused by either SARS-CoV-2 infection or drug-induced liver injury. There were a few interstitial mononuclear inflammatory infiltrates, but no other substantial damage in the heart tissue (figure 2D). Peripheral blood was prepared for flow cytometric analysis. We found that the counts of peripheral CD4 and CD8 T cells were substantially reduced, while their status was hyperactivated, as evidenced by the high proportions of HLA-DR (CD4 3·47%) and CD38 (CD8 39·4%) double-positive fractions (appendix p 3). Moreover, there was an increased concentration of highly proinflammatory CCR6+ Th17 in CD4 T cells (appendix p 3). Additionally, CD8 T cells were found to harbour high concentrations of cytotoxic granules, in which 31·6% cells were perforin positive, 64·2% cells were granulysin positive, and 30·5% cells were granulysin and perforin double-positive (appendix p 3). Our results imply that overactivation of T cells, manifested by increase of Th17 and high cytotoxicity of CD8 T cells, accounts for, in part, the severe immune injury in this patient. X-ray images showed rapid progression of pneumonia and some differences between the left and right lung. In addition, the liver tissue showed moderate microvesicular steatosis and mild lobular activity, but there was no conclusive evidence to support SARS-CoV-2 infection or drug-induced liver injury as the cause. There were no obvious histological changes seen in heart tissue, suggesting that SARS-CoV-2 infection might not directly impair the heart. Although corticosteroid treatment is not routinely recommended to be used for SARS-CoV-2 pneumonia, 1 according to our pathological findings of pulmonary oedema and hyaline membrane formation, timely and appropriate use of corticosteroids together with ventilator support should be considered for the severe patients to prevent ARDS development. Lymphopenia is a common feature in the patients with COVID-19 and might be a critical factor associated with disease severity and mortality. 3 Our clinical and pathological findings in this severe case of COVID-19 can not only help to identify a cause of death, but also provide new insights into the pathogenesis of SARS-CoV-2-related pneumonia, which might help physicians to formulate a timely therapeutic strategy for similar severe patients and reduce mortality. This online publication has been corrected. The corrected version first appeared at thelancet.com/respiratory on February 25, 2020
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                Author and article information

                Journal
                AJN
                Am J Nephrol
                10.1159/issn.0250-8095
                American Journal of Nephrology
                S. Karger AG
                0250-8095
                1421-9670
                2020
                July 2020
                29 June 2020
                : 51
                : 7
                : 576-578
                Affiliations
                Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China
                Author notes
                *Prof. Zuojiong Gong, Department of Infectious Diseases, Renmin Hospital of Wuhan University, 238, Jiefang Road, Wuchang, Wuhan 430060 (China), zjgong@163.com
                Article
                508089 Am J Nephrol 2020;51:576–578
                10.1159/000508089
                32599585
                42ee3316-241e-467a-a4f5-7053bd92b973
                © 2020 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                History
                : 20 April 2020
                : 20 April 2020
                Page count
                Pages: 3
                Categories
                Letter to the Editor

                Cardiovascular Medicine,Nephrology
                Cardiovascular Medicine, Nephrology

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