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The spatiotemporal trend of renal involvement in COVID-19: A pooled analysis of 17 134 patients

  • Author Footnotes
    1 Yi-Fu Feng and Kun-Peng Wang contributed equally as co-first authors.
    Yi-Fu Feng
    Footnotes
    1 Yi-Fu Feng and Kun-Peng Wang contributed equally as co-first authors.
    Affiliations
    Department of General Surgery, Taizhou Central Hospital, Taizhou 318000, China
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  • Author Footnotes
    1 Yi-Fu Feng and Kun-Peng Wang contributed equally as co-first authors.
    Kun-Peng Wang
    Footnotes
    1 Yi-Fu Feng and Kun-Peng Wang contributed equally as co-first authors.
    Affiliations
    Department of General Surgery, Taizhou Central Hospital, Taizhou 318000, China
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  • Jing-Gang Mo
    Affiliations
    Department of General Surgery, Taizhou Central Hospital, Taizhou 318000, China
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  • Ying-He Xu
    Affiliations
    Department of Intensive Care Unit, Taizhou Central Hospital, Taizhou 318000, China
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  • Lie-Zhi Wang
    Affiliations
    Department of General Surgery, Taizhou Central Hospital, Taizhou 318000, China
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  • Chong Jin
    Affiliations
    Department of General Surgery, Taizhou Central Hospital, Taizhou 318000, China
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  • Xiang Chen
    Affiliations
    Department of Anesthesia, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510655, China

    Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha 410008, China

    Department of Hepatobiliary and Pancreatic Surgery, The Third Xiangya Hospital, Central South University, Changsha 410013, China
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  • Bin Yi
    Correspondence
    Corresponding author at: Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha 410008, China; Department of Cardiothoracic Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China.
    Affiliations
    Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha 410008, China

    Department of Cardiothoracic Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China
    Search for articles by this author
  • Author Footnotes
    1 Yi-Fu Feng and Kun-Peng Wang contributed equally as co-first authors.
Open AccessPublished:April 03, 2021DOI:https://doi.org/10.1016/j.ijid.2021.03.082

      Highlights

      • Renal involvement in COVID-19 has become an increasingly serious problem over time.
      • Spatial differences were found to be significant in renal involvement superimposed COVID-19.
      • Renal involvement may increase the risk of severe disease and mortality in COVID-19 patients.

      Abstract

      Background

      The spatiotemporal trend of renal involvement in coronavirus disease 2019 (COVID-19) patients is still unclear. Therefore, the aim of this study was to reveal the dynamics of renal involvement superimposed COVID-19 according to time and space.

      Methods

      COVID-19 patients reporting renal involvement were included in this study. The following information was collected from relevant articles: first author, patient demographics, patient enrollment period, location, definition of acute kidney injury (AKI), prevalence of AKI, and use of renal replacement therapy (RRT).

      Results

      A total of 17 134 patients were finally included. The overall prevalence of AKI in COVID-19 patients was 19%, with 7% of them undergoing RRT. The overall risk of AKI in patients enrolled before March 1, 2020 (9%) was significantly lower than that after March 1, 2020 (36%) (P < 0.00001). Moreover, the overall risk of AKI outside Asia (35%) was significantly higher than that in Asia (10%) (P < 0.00001). Additionally, similar to patients requiring RRT, AKI patients were more likely to become seriously ill or even to die (P < 0.00001).

      Conclusions

      This study found that renal involvement superimposed COVID-19, a comorbidity portending a poor prognosis, has become an increasingly serious problem over time and is more common outside Asia. Thus, more attention should be paid to the management of this specific group of patients.

      Keywords

      Introduction

      Coronavirus disease 2019 (COVID-19) is a novel respiratory infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which has reopened the issue of the role and importance of coronaviruses in human pathology (
      • World Health Organization
      Naming the coronavirus disease (COVID-19) and the virus that causes it.
      ). In fact, only seven coronaviruses are known to be zoonotic, with the ability to jump from animals to humans. Four of them cause mild illnesses, such as the common cold, while the other three types have had more catastrophic consequences: severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and now SARS-CoV-2 (
      • Čivljak R.
      • Markotić A.
      • Kuzman I.
      The third coronavirus epidemic in the third millennium: what’s next?.
      ).
      Taking account of the alarming levels of spread and severity worldwide, COVID-19 has been declared as a pandemic by the World Health Organization (WHO), and no country could manage alone or stand aloof (
      • World Health Organization
      WHO declares COVID-19 a pandemic.
      ). The numbers of affected countries, cases, and deaths are climbing sharply, at an alarming rate. Up to June 30, 2020, more than 210 countries and territories had been affected by the crisis, with a total of 10 185 374 confirmed cases and 503 962 deaths (
      • World Health Organization
      Coronavirus disease (COVID-2019) situation reports-162.
      ). Moreover, COVID-19 has had a great impact on mental health, education, finance, transportation, the economy, and so on (
      • Codagnone C.
      • Bogliacino F.
      • Gomez C.
      • Charris R.
      • Montealegre F.
      • Liva G.
      • et al.
      Assessing concerns for the economic consequence of the COVID-19 response and mental health problems associated with economic vulnerability and negative economic shock in Italy, Spain, and the United Kingdom.
      ,
      • Gautam R.
      • Sharma M.
      2019-nCoV pandemic: a disruptive and stressful atmosphere for Indian academic fraternity.
      ,
      • McKee M.
      • Stuckler D.
      If the world fails to protect the economy, COVID-19 will damage health not just now but also in the future.
      ,
      • Sharma M.
      • Sharma S.
      The rising number of COVID-19 cases reflecting growing search trend and concern of people: a Google trend analysis of eight major countries.
      ,
      • Sharma S.
      • Sharma M.
      • Singh G.
      A chaotic and stressed environment for 2019-nCoV suspected, infected and other people in India: fear of mass destruction and causality.
      ).
      Early screening for clinical suspicion could effectively control this spread. In addition to the common symptoms of fever, fatigue, and an unproductive cough, the clinical manifestations in patients with COVID-19 include diarrhea, septic shock, and even multiple organ dysfunction syndromes (
      • Wang C.
      • Horby P.W.
      • Hayden F.G.
      • Gao G.F.
      A novel coronavirus outbreak of global health concern.
      ). Comorbidity superimposed COVID-19 is usually an indicator of more severe disability and a lower survival rate in affected patients. Although a recent study has suggested that renal involvement is uncommon in COVID-19 (
      • Wang D.
      • Yin Y.
      • Hu C.
      • Liu X.
      • Zhang X.
      • Zhou S.
      • et al.
      Clinical course and outcome of 107 patients infected with the novel coronavirus, SARS-CoV-2, discharged from two hospitals in Wuhan, China.
      ), it may lead to a poor prognosis when acute kidney injury (AKI) develops in COVID-19 patients. Furthermore, few studies have focused on the spatiotemporal trends of renal involvement superimposed COVID-19. Therefore, the aim of this study was to conduct a pooled analysis of available studies reporting renal involvement in COVID-19 based on the space–time structure.

      Methods

      This study was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (
      • Moher D.
      • Liberati A.
      • Tetzlaff J.
      • Altman D.G.
      Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
      ).

      Search strategy

      All studies reporting renal involvement in COVID-19 patients and published up to June 30, 2020 were identified in the PubMed, Scopus, and Web of Science databases. The search words were “COVID-19”, “coronavirus disease 2019”, “SARS-CoV-2”, “severe acute respiratory syndrome coronavirus 2”, “nCoV”, “novel coronavirus”, “corona virus”, “kidney”, “renal”, and “nephrology”. References cited in the retrieved original articles were also reviewed. There was no restriction on language. Two investigators (YFF and KPW) independently analyzed these publications by title and abstract. Full texts were reviewed to identify any potentially relevant studies.

      Study selection and outcome measures

      To be included in this study, the articles had to meet the following criteria: (1) study with an observational design; (2) study sample of more than 10 patients; (3) study patients with confirmed SARS-CoV-2 infection; (4) study reporting the prevalence of AKI in COVID-19 patients.
      The following articles were excluded: (1) repeatedly published articles; (2) editorial, commentary, guidance, perspective, reply, review, and single case reports; (3) studies containing uncertain data; (4) studies lacking available data; and (5) studies on other coronavirus diseases, such as SARS and MERS.
      The primary outcome in this study was the prevalence of AKI superimposed COVID-19. The requirement of renal replacement therapy (RRT) was the secondary outcome.

      Data extraction and quality assessment

      Two investigators (YFF and KPW) independently conducted the data extraction and quality assessment; any disagreement was settled by a third investigator (BY). The following information was retrieved from each article: first author, patient demographics, patient enrollment period, location, definition of AKI, prevalence of AKI, and requirement for RRT. If necessary, the corresponding authors of included studies were contacted directly for additional data. Disease severity and mortality were defined according to the studies. If the authors did not report the severity classification of COVID-19, the patients who developed acute respiratory distress syndrome, needed mechanical ventilation, or were admitted to the intensive care unit were classified as severe cases. The risk of bias was assessed using the quality assessment tool for case-series studies published by the National Institutes of Health, which poses nine questions, such as the study objective, study population, and study intervention (
      • Mao R.
      • Qiu Y.
      • He J.
      • Tan J.
      • Li X.
      • Liang J.
      • et al.
      Manifestations and prognosis of gastrointestinal and liver involvement in patients with COVID-19: a systematic review and meta-analysis.
      ).

      Data analysis

      Review Manager version 5.3 (Cochrane Collaboration) and Microsoft Excel (Microsoft Corporation) were used for the data analysis. Subgroup analyses were performed according to (1) the location of the study; (2) the patient enrollment period; (3) the severity of the disease; and (4) the mortality of the disease. To calculate the pooled estimated prevalence with 95% confidence intervals (CI) of AKI and RRT in COVID-19 patients, two simple formulas enumerated by Chen et al. to evaluate the probability and its standard error were employed (
      • Chen Y.
      • Du L.
      • Geng X.
      • Liu G.
      Implement meta-analysis with non-comparative binary data in RevMan Sofware.
      ). Risk ratios (RRs) with 95% CI of the outcome measures were used for the subgroup analyses based on disease severity and mortality. For the robustness of the pooled effects, the meta-analyses were conducted with the random-effects model by inverse variance method. Publication bias was examined by the symmetry of the funnel plot (
      • Mao R.
      • Qiu Y.
      • He J.
      • Tan J.
      • Li X.
      • Liang J.
      • et al.
      Manifestations and prognosis of gastrointestinal and liver involvement in patients with COVID-19: a systematic review and meta-analysis.
      ). Significant heterogeneity within and/or between studies was defined when I2 > 50%; otherwise, the heterogeneity was not considered substantial. P < 0.05 was considered statistically significant (
      • Yi B.
      • Luo J.
      • Jiang Y.
      • Mo S.
      • Xiao X.
      • Chen X.
      • et al.
      Nicorandil for periprocedural myocardial injury in elective percutaneous coronary intervention: a meta-analysis of 10 randomized controlled trials.
      ).

      Results

      Search results

      Initially, 2751 records were retrieved, including 606 from PubMed, 1649 from Scopus, and 496 from Web of Science. After removing 809 duplicate records, 1849 records were also eliminated based on the title and abstract. Finally, following the full-text evaluation of 93 potentially relevant studies, a total of 30 eligible studies were identified for inclusion in this study (
      • Aggarwal S.
      • Garcia-Telles N.
      • Aggarwal G.
      • Lavie C.
      • Lippi G.
      • Henry B.M.
      Clinical features, laboratory characteristics, and outcomes of patients hospitalized with coronavirus disease 2019 (COVID-19): early report from the United States.
      ,
      • Antinori S.
      • Cossu M.V.
      • Ridolfo A.L.
      • Rech R.
      • Bonazzetti C.
      • Pagani G.
      • et al.
      Compassionate remdesivir treatment of severe Covid-19 pneumonia in intensive care unit (ICU) and non-ICU patients: clinical outcome and differences in post-treatment hospitalisation status.
      ,
      • Argenziano M.G.
      • Bruce S.L.
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      • Baldwin M.R.
      • Barr R.G.
      • et al.
      Characterization and clinical course of 1000 patients with coronavirus disease 2019 in New York: retrospective case series.
      ,
      • Bhargava A.
      • Fukushima E.A.
      • Levine M.
      • Zhao W.
      • Tanveer F.
      • Szpunar S.M.
      • et al.
      Predictors for severe COVID-19 infection.
      ,
      • Cao J.
      • Hu X.
      • Cheng W.
      • Yu L.
      • Tu W.J.
      • Liu Q.
      Clinical features and short-term outcomes of 18 patients with corona virus disease 2019 in intensive care unit.
      ,
      • Chen G.
      • Wu D.
      • Guo W.
      • Cao Y.
      • Huang D.
      • Wang H.
      • et al.
      Clinical and immunological features of severe and moderate coronavirus disease 2019.
      ,
      • Chen T.
      • Wu D.
      • Chen H.
      • Yan W.
      • Yang D.
      • Chen G.
      • et al.
      Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study.
      ,
      • Cheng Y.
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      • Wang K.
      • Zhang M.
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      • Dong L.
      • et al.
      Kidney disease is associated with in-hospital death of patients with COVID-19.
      ,
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      • et al.
      Epidemiology, clinical course, and outcomes of critically ill adults with COVID-19 in New York City: a prospective cohort study.
      ,
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      • Zhou L.
      • et al.
      Clinical characteristics of fatal and recovered cases of coronavirus disease 2019 (COVID-19) in Wuhan, China: a retrospective study.
      ,
      • Hirsch J.S.
      • Ng J.H.
      • Ross D.W.
      • Sharma P.
      • Shah H.H.
      • Barnett R.L.
      • et al.
      Acute kidney injury in patients hospitalized with COVID-19.
      ,
      • Hong K.S.
      • Lee K.H.
      • Chung J.H.
      • Shin K.
      • Choi E.Y.
      • Jin H.J.
      • et al.
      Clinical features and outcomes of 98 patients hospitalized with SARS-CoV-2 infection in Daegu, South Korea: a brief descriptive study.
      ,
      • Li D.
      • Chen Y.
      • Liu H.
      • Jia Y.
      • Li F.
      • Wang W.
      • et al.
      Immune dysfunction leads to mortality and organ injury in patients with COVID-19 in China: insights from ERS-COVID-19 study.
      ,
      • Li X.
      • Wang L.
      • Yan S.
      • Yang F.
      • Xiang L.
      • Zhu J.
      • et al.
      Clinical characteristics of 25 death cases with COVID-19: a retrospective review of medical records in a single medical center, Wuhan, China.
      ,
      • Li Y.
      • Hu Y.
      • Yu J.
      • Ma T.
      Retrospective analysis of laboratory testing in 54 patients with severe- or critical-type 2019 novel coronavirus pneumonia.
      ,
      • Malberti F.
      • Pecchini P.
      • Marchi G.
      • Foramitti M.
      When a nephrology ward becomes a COVID-19 ward: the Cremona experience.
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      • Pei G.
      • Zhang Z.
      • Peng J.
      • Liu L.
      • Zhang C.
      • Yu C.
      • et al.
      Renal involvement and early prognosis in patients with COVID-19 pneumonia.
      ,
      • Richardson S.
      • Hirsch J.S.
      • Narasimhan M.
      • Crawford J.M.
      • McGinn T.
      • Davidson K.W.
      • et al.
      Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area.
      ,
      • Shi M.
      • Chen L.
      • Yang Y.
      • Zhang J.
      • Xu J.
      • Xu G.
      • et al.
      Analysis of clinical features and outcomes of 161 patients with severe and critical COVID-19: a multicenter descriptive study.
      ,
      • Shi S.
      • Qin M.
      • Shen B.
      • Cai Y.
      • Liu T.
      • Yang F.
      • et al.
      Association of cardiac injury with mortality in hospitalized patients with COVID-19 in Wuhan, China.
      ,
      • Wang L.
      • Li X.
      • Chen H.
      • Yan S.
      • Li D.
      • Li Y.
      • et al.
      Coronavirus disease 19 infection does not result in acute kidney injury: an analysis of 116 hospitalized patients from Wuhan, China.
      ,
      • Yang F.
      • Shi S.
      • Zhu J.
      • Shi J.
      • Dai K.
      • Chen X.
      Analysis of 92 deceased patients with COVID-19.
      ,
      • Yang Q.
      • Xie L.
      • Zhang W.
      • Zhao L.
      • Wu H.
      • Jiang J.
      • et al.
      Analysis of the clinical characteristics, drug treatments and prognoses of 136 patients with coronavirus disease 2019.
      ,
      • Yang R.
      • Gui X.
      • Zhang Y.
      • Xiong Y.
      The role of essential organ-based comorbidities in the prognosis of COVID-19 infection patients.
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      Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study.
      ,
      • Yu Y.
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      • Yang X.
      • Xu L.
      • et al.
      Patients with COVID-19 in 19 ICUs in Wuhan, China: a cross-sectional study.
      ,
      • Zhang G.
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      • Luo L.
      • Fang F.
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      Clinical features and short-term outcomes of 221 patients with COVID-19 in Wuhan, China.
      ,
      • Zhang X.
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      • Zhang S.
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      Epidemiological, clinical characteristics of cases of SARS-CoV-2 infection with abnormal imaging findings.
      ,
      • Zhao X.
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      Clinical characteristics of patients with 2019 coronavirus disease in a non-Wuhan area of Hubei Province, China: a retrospective study.
      ,
      • Zheng Y.
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      • Fang X.
      • et al.
      Clinical characteristics of 34 COVID-19 patients admitted to intensive care unit in Hangzhou, China.
      ) (Figure 1).
      Figure 1
      Figure 1Flow diagram of the study selection.

      Study characteristics

      Overall, the 30 studies included 17 134 patients. Thirteen studies described the prevalence of AKI in patients with severe versus non-severe COVID-19 (
      • Aggarwal S.
      • Garcia-Telles N.
      • Aggarwal G.
      • Lavie C.
      • Lippi G.
      • Henry B.M.
      Clinical features, laboratory characteristics, and outcomes of patients hospitalized with coronavirus disease 2019 (COVID-19): early report from the United States.
      ,
      • Antinori S.
      • Cossu M.V.
      • Ridolfo A.L.
      • Rech R.
      • Bonazzetti C.
      • Pagani G.
      • et al.
      Compassionate remdesivir treatment of severe Covid-19 pneumonia in intensive care unit (ICU) and non-ICU patients: clinical outcome and differences in post-treatment hospitalisation status.
      ,
      • Argenziano M.G.
      • Bruce S.L.
      • Slater C.L.
      • Tiao J.R.
      • Baldwin M.R.
      • Barr R.G.
      • et al.
      Characterization and clinical course of 1000 patients with coronavirus disease 2019 in New York: retrospective case series.
      ,
      • Bhargava A.
      • Fukushima E.A.
      • Levine M.
      • Zhao W.
      • Tanveer F.
      • Szpunar S.M.
      • et al.
      Predictors for severe COVID-19 infection.
      ,
      • Cao J.
      • Hu X.
      • Cheng W.
      • Yu L.
      • Tu W.J.
      • Liu Q.
      Clinical features and short-term outcomes of 18 patients with corona virus disease 2019 in intensive care unit.
      ,
      • Chen G.
      • Wu D.
      • Guo W.
      • Cao Y.
      • Huang D.
      • Wang H.
      • et al.
      Clinical and immunological features of severe and moderate coronavirus disease 2019.
      ,
      • Hirsch J.S.
      • Ng J.H.
      • Ross D.W.
      • Sharma P.
      • Shah H.H.
      • Barnett R.L.
      • et al.
      Acute kidney injury in patients hospitalized with COVID-19.
      ,
      • Hong K.S.
      • Lee K.H.
      • Chung J.H.
      • Shin K.
      • Choi E.Y.
      • Jin H.J.
      • et al.
      Clinical features and outcomes of 98 patients hospitalized with SARS-CoV-2 infection in Daegu, South Korea: a brief descriptive study.
      ,
      • Pei G.
      • Zhang Z.
      • Peng J.
      • Liu L.
      • Zhang C.
      • Yu C.
      • et al.
      Renal involvement and early prognosis in patients with COVID-19 pneumonia.
      ,
      • Yang Q.
      • Xie L.
      • Zhang W.
      • Zhao L.
      • Wu H.
      • Jiang J.
      • et al.
      Analysis of the clinical characteristics, drug treatments and prognoses of 136 patients with coronavirus disease 2019.
      ;
      • Zhang G.
      • Hu C.
      • Luo L.
      • Fang F.
      • Chen Y.
      • Li J.
      • et al.
      Clinical features and short-term outcomes of 221 patients with COVID-19 in Wuhan, China.
      ;
      • Zhao X.
      • Xu X.
      • Yin H.
      • Hu Q.
      • Xiong T.
      • Tang Y.
      • et al.
      Clinical characteristics of patients with 2019 coronavirus disease in a non-Wuhan area of Hubei Province, China: a retrospective study.
      ,
      • Zheng Y.
      • Sun L.
      • Xu M.
      • Pan J.
      • Zhang Y.
      • Fang X.
      • et al.
      Clinical characteristics of 34 COVID-19 patients admitted to intensive care unit in Hangzhou, China.
      ) and five studies described the ratio of the probability of AKI in COVID-19 survivors versus non-survivors (
      • Chen T.
      • Wu D.
      • Chen H.
      • Yan W.
      • Yang D.
      • Chen G.
      • et al.
      Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study.
      ,
      • Deng Y.
      • Liu W.
      • Liu K.
      • Fang Y.
      • Shang J.
      • Zhou L.
      • et al.
      Clinical characteristics of fatal and recovered cases of coronavirus disease 2019 (COVID-19) in Wuhan, China: a retrospective study.
      ,
      • Richardson S.
      • Hirsch J.S.
      • Narasimhan M.
      • Crawford J.M.
      • McGinn T.
      • Davidson K.W.
      • et al.
      Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area.
      ,
      • Wang L.
      • Li X.
      • Chen H.
      • Yan S.
      • Li D.
      • Li Y.
      • et al.
      Coronavirus disease 19 infection does not result in acute kidney injury: an analysis of 116 hospitalized patients from Wuhan, China.
      ,
      • Yang X.
      • Yu Y.
      • Xu J.
      • Shu H.
      • Xia J.
      • Liu H.
      • et al.
      Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study.
      ). In the majority of studies, AKI was defined according to the ‘Kidney Disease: Improving Global Outcomes’ (KDIGO) criteria (
      • Yi B.
      • Chen X.
      • Shi H.
      • Lin T.
      • Lin H.
      • Xu Y.
      • et al.
      Remote ischaemic preconditioning reduces acute kidney injury in adult patients undergoing cardiac surgery with cardiopulmonary bypass: a meta-analysis.
      ).
      The patients were enrolled during different periods in these studies: 20 studies enrolled patients before March 1, 2020 (
      • Cao J.
      • Hu X.
      • Cheng W.
      • Yu L.
      • Tu W.J.
      • Liu Q.
      Clinical features and short-term outcomes of 18 patients with corona virus disease 2019 in intensive care unit.
      ,
      • Chen G.
      • Wu D.
      • Guo W.
      • Cao Y.
      • Huang D.
      • Wang H.
      • et al.
      Clinical and immunological features of severe and moderate coronavirus disease 2019.
      ,
      • Chen T.
      • Wu D.
      • Chen H.
      • Yan W.
      • Yang D.
      • Chen G.
      • et al.
      Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study.
      ,
      • Cheng Y.
      • Luo R.
      • Wang K.
      • Zhang M.
      • Wang Z.
      • Dong L.
      • et al.
      Kidney disease is associated with in-hospital death of patients with COVID-19.
      ,
      • Deng Y.
      • Liu W.
      • Liu K.
      • Fang Y.
      • Shang J.
      • Zhou L.
      • et al.
      Clinical characteristics of fatal and recovered cases of coronavirus disease 2019 (COVID-19) in Wuhan, China: a retrospective study.
      ,
      • Li D.
      • Chen Y.
      • Liu H.
      • Jia Y.
      • Li F.
      • Wang W.
      • et al.
      Immune dysfunction leads to mortality and organ injury in patients with COVID-19 in China: insights from ERS-COVID-19 study.
      ,
      • Li X.
      • Wang L.
      • Yan S.
      • Yang F.
      • Xiang L.
      • Zhu J.
      • et al.
      Clinical characteristics of 25 death cases with COVID-19: a retrospective review of medical records in a single medical center, Wuhan, China.
      ,
      • Li Y.
      • Hu Y.
      • Yu J.
      • Ma T.
      Retrospective analysis of laboratory testing in 54 patients with severe- or critical-type 2019 novel coronavirus pneumonia.
      ,
      • Pei G.
      • Zhang Z.
      • Peng J.
      • Liu L.
      • Zhang C.
      • Yu C.
      • et al.
      Renal involvement and early prognosis in patients with COVID-19 pneumonia.
      ,
      • Shi M.
      • Chen L.
      • Yang Y.
      • Zhang J.
      • Xu J.
      • Xu G.
      • et al.
      Analysis of clinical features and outcomes of 161 patients with severe and critical COVID-19: a multicenter descriptive study.
      ,
      • Shi S.
      • Qin M.
      • Shen B.
      • Cai Y.
      • Liu T.
      • Yang F.
      • et al.
      Association of cardiac injury with mortality in hospitalized patients with COVID-19 in Wuhan, China.
      ,
      • Wang L.
      • Li X.
      • Chen H.
      • Yan S.
      • Li D.
      • Li Y.
      • et al.
      Coronavirus disease 19 infection does not result in acute kidney injury: an analysis of 116 hospitalized patients from Wuhan, China.
      ,
      • Yang F.
      • Shi S.
      • Zhu J.
      • Shi J.
      • Dai K.
      • Chen X.
      Analysis of 92 deceased patients with COVID-19.
      ,
      • Yang Q.
      • Xie L.
      • Zhang W.
      • Zhao L.
      • Wu H.
      • Jiang J.
      • et al.
      Analysis of the clinical characteristics, drug treatments and prognoses of 136 patients with coronavirus disease 2019.
      ,
      • Yang R.
      • Gui X.
      • Zhang Y.
      • Xiong Y.
      The role of essential organ-based comorbidities in the prognosis of COVID-19 infection patients.
      ,
      • Yang X.
      • Yu Y.
      • Xu J.
      • Shu H.
      • Xia J.
      • Liu H.
      • et al.
      Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study.
      ,
      • Yu Y.
      • Xu D.
      • Fu S.
      • Zhang J.
      • Yang X.
      • Xu L.
      • et al.
      Patients with COVID-19 in 19 ICUs in Wuhan, China: a cross-sectional study.
      ,
      • Zhang G.
      • Hu C.
      • Luo L.
      • Fang F.
      • Chen Y.
      • Li J.
      • et al.
      Clinical features and short-term outcomes of 221 patients with COVID-19 in Wuhan, China.
      ,
      • Zhang X.
      • Cai H.
      • Hu J.
      • Lian J.
      • Gu J.
      • Zhang S.
      • et al.
      Epidemiological, clinical characteristics of cases of SARS-CoV-2 infection with abnormal imaging findings.
      ,
      • Zhao X.
      • Xu X.
      • Yin H.
      • Hu Q.
      • Xiong T.
      • Tang Y.
      • et al.
      Clinical characteristics of patients with 2019 coronavirus disease in a non-Wuhan area of Hubei Province, China: a retrospective study.
      ) and six studies enrolled patients after March 1, 2020 (
      • Aggarwal S.
      • Garcia-Telles N.
      • Aggarwal G.
      • Lavie C.
      • Lippi G.
      • Henry B.M.
      Clinical features, laboratory characteristics, and outcomes of patients hospitalized with coronavirus disease 2019 (COVID-19): early report from the United States.
      ,
      • Argenziano M.G.
      • Bruce S.L.
      • Slater C.L.
      • Tiao J.R.
      • Baldwin M.R.
      • Barr R.G.
      • et al.
      Characterization and clinical course of 1000 patients with coronavirus disease 2019 in New York: retrospective case series.
      ,
      • Bhargava A.
      • Fukushima E.A.
      • Levine M.
      • Zhao W.
      • Tanveer F.
      • Szpunar S.M.
      • et al.
      Predictors for severe COVID-19 infection.
      ,
      • Cummings M.J.
      • Baldwin M.R.
      • Abrams D.
      • Jacobson S.D.
      • Meyer B.J.
      • Balough E.M.
      • et al.
      Epidemiology, clinical course, and outcomes of critically ill adults with COVID-19 in New York City: a prospective cohort study.
      ,
      • Hirsch J.S.
      • Ng J.H.
      • Ross D.W.
      • Sharma P.
      • Shah H.H.
      • Barnett R.L.
      • et al.
      Acute kidney injury in patients hospitalized with COVID-19.
      ,
      • Richardson S.
      • Hirsch J.S.
      • Narasimhan M.
      • Crawford J.M.
      • McGinn T.
      • Davidson K.W.
      • et al.
      Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area.
      ).
      In addition, the locations differed across the 30 studies: one was from South Korea (
      • Hong K.S.
      • Lee K.H.
      • Chung J.H.
      • Shin K.
      • Choi E.Y.
      • Jin H.J.
      • et al.
      Clinical features and outcomes of 98 patients hospitalized with SARS-CoV-2 infection in Daegu, South Korea: a brief descriptive study.
      ), two from Italy (
      • Antinori S.
      • Cossu M.V.
      • Ridolfo A.L.
      • Rech R.
      • Bonazzetti C.
      • Pagani G.
      • et al.
      Compassionate remdesivir treatment of severe Covid-19 pneumonia in intensive care unit (ICU) and non-ICU patients: clinical outcome and differences in post-treatment hospitalisation status.
      ,
      • Malberti F.
      • Pecchini P.
      • Marchi G.
      • Foramitti M.
      When a nephrology ward becomes a COVID-19 ward: the Cremona experience.
      ), six from the United States (
      • Aggarwal S.
      • Garcia-Telles N.
      • Aggarwal G.
      • Lavie C.
      • Lippi G.
      • Henry B.M.
      Clinical features, laboratory characteristics, and outcomes of patients hospitalized with coronavirus disease 2019 (COVID-19): early report from the United States.
      ,
      • Argenziano M.G.
      • Bruce S.L.
      • Slater C.L.
      • Tiao J.R.
      • Baldwin M.R.
      • Barr R.G.
      • et al.
      Characterization and clinical course of 1000 patients with coronavirus disease 2019 in New York: retrospective case series.
      ,
      • Bhargava A.
      • Fukushima E.A.
      • Levine M.
      • Zhao W.
      • Tanveer F.
      • Szpunar S.M.
      • et al.
      Predictors for severe COVID-19 infection.
      ,
      • Cummings M.J.
      • Baldwin M.R.
      • Abrams D.
      • Jacobson S.D.
      • Meyer B.J.
      • Balough E.M.
      • et al.
      Epidemiology, clinical course, and outcomes of critically ill adults with COVID-19 in New York City: a prospective cohort study.
      ,
      • Hirsch J.S.
      • Ng J.H.
      • Ross D.W.
      • Sharma P.
      • Shah H.H.
      • Barnett R.L.
      • et al.
      Acute kidney injury in patients hospitalized with COVID-19.
      ,
      • Richardson S.
      • Hirsch J.S.
      • Narasimhan M.
      • Crawford J.M.
      • McGinn T.
      • Davidson K.W.
      • et al.
      Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area.
      ), and the others were from China (
      • Cao J.
      • Hu X.
      • Cheng W.
      • Yu L.
      • Tu W.J.
      • Liu Q.
      Clinical features and short-term outcomes of 18 patients with corona virus disease 2019 in intensive care unit.
      ,
      • Chen G.
      • Wu D.
      • Guo W.
      • Cao Y.
      • Huang D.
      • Wang H.
      • et al.
      Clinical and immunological features of severe and moderate coronavirus disease 2019.
      ,
      • Chen T.
      • Wu D.
      • Chen H.
      • Yan W.
      • Yang D.
      • Chen G.
      • et al.
      Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study.
      ,
      • Cheng Y.
      • Luo R.
      • Wang K.
      • Zhang M.
      • Wang Z.
      • Dong L.
      • et al.
      Kidney disease is associated with in-hospital death of patients with COVID-19.
      ,
      • Deng Y.
      • Liu W.
      • Liu K.
      • Fang Y.
      • Shang J.
      • Zhou L.
      • et al.
      Clinical characteristics of fatal and recovered cases of coronavirus disease 2019 (COVID-19) in Wuhan, China: a retrospective study.
      ,
      • Li D.
      • Chen Y.
      • Liu H.
      • Jia Y.
      • Li F.
      • Wang W.
      • et al.
      Immune dysfunction leads to mortality and organ injury in patients with COVID-19 in China: insights from ERS-COVID-19 study.
      ,
      • Li X.
      • Wang L.
      • Yan S.
      • Yang F.
      • Xiang L.
      • Zhu J.
      • et al.
      Clinical characteristics of 25 death cases with COVID-19: a retrospective review of medical records in a single medical center, Wuhan, China.
      ,
      • Li Y.
      • Hu Y.
      • Yu J.
      • Ma T.
      Retrospective analysis of laboratory testing in 54 patients with severe- or critical-type 2019 novel coronavirus pneumonia.
      ,
      • Pei G.
      • Zhang Z.
      • Peng J.
      • Liu L.
      • Zhang C.
      • Yu C.
      • et al.
      Renal involvement and early prognosis in patients with COVID-19 pneumonia.
      ,
      • Shi M.
      • Chen L.
      • Yang Y.
      • Zhang J.
      • Xu J.
      • Xu G.
      • et al.
      Analysis of clinical features and outcomes of 161 patients with severe and critical COVID-19: a multicenter descriptive study.
      ,
      • Shi S.
      • Qin M.
      • Shen B.
      • Cai Y.
      • Liu T.
      • Yang F.
      • et al.
      Association of cardiac injury with mortality in hospitalized patients with COVID-19 in Wuhan, China.
      ,
      • Wang L.
      • Li X.
      • Chen H.
      • Yan S.
      • Li D.
      • Li Y.
      • et al.
      Coronavirus disease 19 infection does not result in acute kidney injury: an analysis of 116 hospitalized patients from Wuhan, China.
      ,
      • Yang F.
      • Shi S.
      • Zhu J.
      • Shi J.
      • Dai K.
      • Chen X.
      Analysis of 92 deceased patients with COVID-19.
      ,
      • Yang Q.
      • Xie L.
      • Zhang W.
      • Zhao L.
      • Wu H.
      • Jiang J.
      • et al.
      Analysis of the clinical characteristics, drug treatments and prognoses of 136 patients with coronavirus disease 2019.
      ,
      • Yang R.
      • Gui X.
      • Zhang Y.
      • Xiong Y.
      The role of essential organ-based comorbidities in the prognosis of COVID-19 infection patients.
      ,
      • Yang X.
      • Yu Y.
      • Xu J.
      • Shu H.
      • Xia J.
      • Liu H.
      • et al.
      Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study.
      ,
      • Yu Y.
      • Xu D.
      • Fu S.
      • Zhang J.
      • Yang X.
      • Xu L.
      • et al.
      Patients with COVID-19 in 19 ICUs in Wuhan, China: a cross-sectional study.
      ,
      • Zhang G.
      • Hu C.
      • Luo L.
      • Fang F.
      • Chen Y.
      • Li J.
      • et al.
      Clinical features and short-term outcomes of 221 patients with COVID-19 in Wuhan, China.
      ,
      • Zhang X.
      • Cai H.
      • Hu J.
      • Lian J.
      • Gu J.
      • Zhang S.
      • et al.
      Epidemiological, clinical characteristics of cases of SARS-CoV-2 infection with abnormal imaging findings.
      ,
      • Zhao X.
      • Xu X.
      • Yin H.
      • Hu Q.
      • Xiong T.
      • Tang Y.
      • et al.
      Clinical characteristics of patients with 2019 coronavirus disease in a non-Wuhan area of Hubei Province, China: a retrospective study.
      ,
      • Zheng Y.
      • Sun L.
      • Xu M.
      • Pan J.
      • Zhang Y.
      • Fang X.
      • et al.
      Clinical characteristics of 34 COVID-19 patients admitted to intensive care unit in Hangzhou, China.
      ).
      The quality score of all studies ranged from 5 to 6, representing a moderate risk of bias (Supplementary material Table S1). The main characteristics and quality assessment scores of these studies are summarized in Table 1.
      Table 1Characteristics of the included studies.
      First authorNumber of patientsDuration of enrolmentLocationSeverity/survival reportedAKI definitionQuality score
      A. Bhargava et al.197Mar 8, 2020–Apr 8, 2020USASeverity reportedKDIGO5
      D. Li et al.163Jan 31, 2020–Feb 18, 2020ChinaNRKDIGO5
      D. Wang et al.107Jan 2020–Feb 10, 2020ChinaSurvival reportedKDIGO5
      F. Malberti et al.51Feb 20, 2020–Apr 15, 2020ItalyNRKDIGO5
      F. Yang et al.92Jan 6, 2020–Feb 25, 2020ChinaNRElevated SCr5
      G. Chen et al.21Late Dec 2019–Jan 27, 2020ChinaSeverity reportedKDIGO5
      G. Pei et al.333Jan 28, 2020–Feb 9, 2020ChinaSeverity reportedKDIGO5
      G. Zhang et al.221Jan 2, 2020–Feb 10, 2020ChinaSeverity reportedNR5
      J. Cao et al.102Jan 3, 2020–Feb 1, 2020ChinaSeverity reportedNR5
      J. Hirsch et al.5449Mar 1, 2020–Apr 5, 2020USASeverity reportedKDIGO5
      K. Hong et al.98Dec 2019– Mar 29, 2020South KoreaSeverity reportedKDIGO6
      M. Argenziano et al.1000Mar 1, 2020–Apr 5, 2020USASeverity reportedNR6
      M. Cummings et al.257Mar 2, 2020–Apr 1, 2020USANRNeed for RRT5
      M. Shi et al.161Jan 1, 2020–Mar 1, 2020ChinaNRNR6
      Q. Yang et al.136Jan 28, 2020–Feb 12, 2020ChinaSeverity reportedNR5
      R. Yang et al.212Jan 11, 2020–Mar 16, 2020ChinaNRKDIGO6
      S. Aggarwal et al.16Mar 1, 2020–Apr 4, 2020USASeverity reportedElevated SCr5
      S. Antinori et al.35Feb 23, 2020–Mar 20, 2020ItalySeverity reportedElevated SCr6
      S. Richardson et al.5700Mar 1, 2020–Apr 4, 2020USASurvival reportedElevated SCr6
      S. Shi et al.416Jan 20, 2020–Feb 10, 2020ChinaNRKDIGO6
      T. Chen et al.274Jan 13, 2020–Feb 12, 2020ChinaSurvival reportedKDIGO5
      X. Li et al.25Jan 14, 2020–Feb 13, 2020ChinaNRElevated SCr/BUN5
      X. Yang et al.52Dec 24, 2019–Jan 26, 2020ChinaSurvival reportedKDIGO5
      X. Zhang et al.645Jan 17, 2020–Feb 8, 2020ChinaNRNR5
      X. Zhao et al.91Jan 16, 2020–Feb 10, 2020ChinaSeverity reportedElevated SCr/UA5
      Y. Cheng et al.701Jan 28, 2020–Feb 11, 2020ChinaNRKDIGO6
      Y. Deng et al.225Jan 1, 2020–Feb 21, 2020ChinaSurvival reportedNR5
      Y. Li et al.54Jan 28, 2020–Feb 11, 2020ChinaNRReduced eGFR5
      Y. Yu et al.226Feb 26, 2020– Feb 27, 2020ChinaNRKDIGO5
      Y. Zheng et al.34Jan 22, 2020–Mar 5, 2020ChinaSeverity reportedKDIGO5
      AKI, acute kidney injury; BUN, blood urea nitrogen; eGFR, estimated glomerular filtration rate; KDIGO, Kidney Disease Improving Global Outcomes; NR, not reported; RRT, renal replacement therapy; SCr, serum creatinine; UA, uric acid.

      Study outcomes

      The prevalence of AKI in the 30 studies varied from 0.3% to 68.8%. AKI occurred in 4197 COVID-19 patients, with a pooled probability of 19% (95% CI 13–24%, I2 = 99%) calculated in the analysis (Figure 2).
      Figure 2
      Figure 2Forest plot of the overall risk of acute kidney injury. (Abbreviations: SE, standard error; IV, inverse variance method; CI, confidence interval).
      Due to the high heterogeneity, the possible confounders in these studies were explored. As reported in Table 1, the 30 studies were conducted over different periods. The subgroup analysis based on the cut-off time point of March 1, 2020 indicated that high heterogeneity existed before and after this time point (Chi-square = 46.29, df = 1, I2 = 97.8%; Table 2). AKI occurred in 329 out of 4256 patients enrolled before March 1, 2020 among 20 studies (
      • Cao J.
      • Hu X.
      • Cheng W.
      • Yu L.
      • Tu W.J.
      • Liu Q.
      Clinical features and short-term outcomes of 18 patients with corona virus disease 2019 in intensive care unit.
      ,
      • Chen G.
      • Wu D.
      • Guo W.
      • Cao Y.
      • Huang D.
      • Wang H.
      • et al.
      Clinical and immunological features of severe and moderate coronavirus disease 2019.
      ,
      • Chen T.
      • Wu D.
      • Chen H.
      • Yan W.
      • Yang D.
      • Chen G.
      • et al.
      Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study.
      ,
      • Cheng Y.
      • Luo R.
      • Wang K.
      • Zhang M.
      • Wang Z.
      • Dong L.
      • et al.
      Kidney disease is associated with in-hospital death of patients with COVID-19.
      ,
      • Deng Y.
      • Liu W.
      • Liu K.
      • Fang Y.
      • Shang J.
      • Zhou L.
      • et al.
      Clinical characteristics of fatal and recovered cases of coronavirus disease 2019 (COVID-19) in Wuhan, China: a retrospective study.
      ,
      • Li D.
      • Chen Y.
      • Liu H.
      • Jia Y.
      • Li F.
      • Wang W.
      • et al.
      Immune dysfunction leads to mortality and organ injury in patients with COVID-19 in China: insights from ERS-COVID-19 study.
      ,
      • Li X.
      • Wang L.
      • Yan S.
      • Yang F.
      • Xiang L.
      • Zhu J.
      • et al.
      Clinical characteristics of 25 death cases with COVID-19: a retrospective review of medical records in a single medical center, Wuhan, China.
      ,
      • Li Y.
      • Hu Y.
      • Yu J.
      • Ma T.
      Retrospective analysis of laboratory testing in 54 patients with severe- or critical-type 2019 novel coronavirus pneumonia.
      ,
      • Pei G.
      • Zhang Z.
      • Peng J.
      • Liu L.
      • Zhang C.
      • Yu C.
      • et al.
      Renal involvement and early prognosis in patients with COVID-19 pneumonia.
      ,
      • Shi M.
      • Chen L.
      • Yang Y.
      • Zhang J.
      • Xu J.
      • Xu G.
      • et al.
      Analysis of clinical features and outcomes of 161 patients with severe and critical COVID-19: a multicenter descriptive study.
      ,
      • Shi S.
      • Qin M.
      • Shen B.
      • Cai Y.
      • Liu T.
      • Yang F.
      • et al.
      Association of cardiac injury with mortality in hospitalized patients with COVID-19 in Wuhan, China.
      ,
      • Wang L.
      • Li X.
      • Chen H.
      • Yan S.
      • Li D.
      • Li Y.
      • et al.
      Coronavirus disease 19 infection does not result in acute kidney injury: an analysis of 116 hospitalized patients from Wuhan, China.
      ,
      • Yang F.
      • Shi S.
      • Zhu J.
      • Shi J.
      • Dai K.
      • Chen X.
      Analysis of 92 deceased patients with COVID-19.
      ,
      • Yang Q.
      • Xie L.
      • Zhang W.
      • Zhao L.
      • Wu H.
      • Jiang J.
      • et al.
      Analysis of the clinical characteristics, drug treatments and prognoses of 136 patients with coronavirus disease 2019.
      ,
      • Yang R.
      • Gui X.
      • Zhang Y.
      • Xiong Y.
      The role of essential organ-based comorbidities in the prognosis of COVID-19 infection patients.
      ,
      • Yang X.
      • Yu Y.
      • Xu J.
      • Shu H.
      • Xia J.
      • Liu H.
      • et al.
      Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study.
      ,
      • Yu Y.
      • Xu D.
      • Fu S.
      • Zhang J.
      • Yang X.
      • Xu L.
      • et al.
      Patients with COVID-19 in 19 ICUs in Wuhan, China: a cross-sectional study.
      ,
      • Zhang G.
      • Hu C.
      • Luo L.
      • Fang F.
      • Chen Y.
      • Li J.
      • et al.
      Clinical features and short-term outcomes of 221 patients with COVID-19 in Wuhan, China.
      ,
      • Zhang X.
      • Cai H.
      • Hu J.
      • Lian J.
      • Gu J.
      • Zhang S.
      • et al.
      Epidemiological, clinical characteristics of cases of SARS-CoV-2 infection with abnormal imaging findings.
      ,
      • Zhao X.
      • Xu X.
      • Yin H.
      • Hu Q.
      • Xiong T.
      • Tang Y.
      • et al.
      Clinical characteristics of patients with 2019 coronavirus disease in a non-Wuhan area of Hubei Province, China: a retrospective study.
      ) and in 3824 out of 12 469 patients after March 1, 2020 among six studies (
      • Aggarwal S.
      • Garcia-Telles N.
      • Aggarwal G.
      • Lavie C.
      • Lippi G.
      • Henry B.M.
      Clinical features, laboratory characteristics, and outcomes of patients hospitalized with coronavirus disease 2019 (COVID-19): early report from the United States.
      ,
      • Argenziano M.G.
      • Bruce S.L.
      • Slater C.L.
      • Tiao J.R.
      • Baldwin M.R.
      • Barr R.G.
      • et al.
      Characterization and clinical course of 1000 patients with coronavirus disease 2019 in New York: retrospective case series.
      ,
      • Bhargava A.
      • Fukushima E.A.
      • Levine M.
      • Zhao W.
      • Tanveer F.
      • Szpunar S.M.
      • et al.
      Predictors for severe COVID-19 infection.
      ,
      • Cummings M.J.
      • Baldwin M.R.
      • Abrams D.
      • Jacobson S.D.
      • Meyer B.J.
      • Balough E.M.
      • et al.
      Epidemiology, clinical course, and outcomes of critically ill adults with COVID-19 in New York City: a prospective cohort study.
      ,
      • Hirsch J.S.
      • Ng J.H.
      • Ross D.W.
      • Sharma P.
      • Shah H.H.
      • Barnett R.L.
      • et al.
      Acute kidney injury in patients hospitalized with COVID-19.
      ,
      • Richardson S.
      • Hirsch J.S.
      • Narasimhan M.
      • Crawford J.M.
      • McGinn T.
      • Davidson K.W.
      • et al.
      Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area.
      ). Overall, there was a significant difference in the pooled risk of AKI between patients enrolled before March 1, 2020 (9%, 95% CI 7–12%) and those enrolled after that time point (36%, 95% CI 28–43%) (P < 0.00001).
      Table 2Subgroup analyses for the overall risk of AKI.
      SubgroupNumber of

      studies
      Number of

      patients
      Cases of AKIPooled probability95% CISubgroup difference
      I2 (%)P-value
      Enrolment duration97.8<0.00001
       Before March 1, 20202042563290.090.07–0.12
       After March 1, 2020612 46938240.360.28–0.43
      Location98.1<0.00001
       Asia2243883450.100.07–0.12
       Non-Asia812 55538520.350.28–0.41
      AKI, acute kidney injury; CI, confidence interval.
      During the analysis, it was observed that the 30 studies were from four countries: South Korea, Italy, the United States, and China. Given that South Korea and China are located in Asia, the subgroup analysis was conducted based on studies in and outside Asia. The test for subgroup differences is shown in Table 2 (Chi-square = 40.29, df = 1, I2 = 97.5%). AKI developed in 345 out of 4388 patients among 22 studies in Asia (
      • Cao J.
      • Hu X.
      • Cheng W.
      • Yu L.
      • Tu W.J.
      • Liu Q.
      Clinical features and short-term outcomes of 18 patients with corona virus disease 2019 in intensive care unit.
      ,
      • Chen G.
      • Wu D.
      • Guo W.
      • Cao Y.
      • Huang D.
      • Wang H.
      • et al.
      Clinical and immunological features of severe and moderate coronavirus disease 2019.
      ,
      • Chen T.
      • Wu D.
      • Chen H.
      • Yan W.
      • Yang D.
      • Chen G.
      • et al.
      Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study.
      ,
      • Cheng Y.
      • Luo R.
      • Wang K.
      • Zhang M.
      • Wang Z.
      • Dong L.
      • et al.
      Kidney disease is associated with in-hospital death of patients with COVID-19.
      ,
      • Deng Y.
      • Liu W.
      • Liu K.
      • Fang Y.
      • Shang J.
      • Zhou L.
      • et al.
      Clinical characteristics of fatal and recovered cases of coronavirus disease 2019 (COVID-19) in Wuhan, China: a retrospective study.
      ,
      • Hong K.S.
      • Lee K.H.
      • Chung J.H.
      • Shin K.
      • Choi E.Y.
      • Jin H.J.
      • et al.
      Clinical features and outcomes of 98 patients hospitalized with SARS-CoV-2 infection in Daegu, South Korea: a brief descriptive study.
      ,
      • Li D.
      • Chen Y.
      • Liu H.
      • Jia Y.
      • Li F.
      • Wang W.
      • et al.
      Immune dysfunction leads to mortality and organ injury in patients with COVID-19 in China: insights from ERS-COVID-19 study.
      ,
      • Li X.
      • Wang L.
      • Yan S.
      • Yang F.
      • Xiang L.
      • Zhu J.
      • et al.
      Clinical characteristics of 25 death cases with COVID-19: a retrospective review of medical records in a single medical center, Wuhan, China.
      ,
      • Li Y.
      • Hu Y.
      • Yu J.
      • Ma T.
      Retrospective analysis of laboratory testing in 54 patients with severe- or critical-type 2019 novel coronavirus pneumonia.
      ,
      • Pei G.
      • Zhang Z.
      • Peng J.
      • Liu L.
      • Zhang C.
      • Yu C.
      • et al.
      Renal involvement and early prognosis in patients with COVID-19 pneumonia.
      ,
      • Shi M.
      • Chen L.
      • Yang Y.
      • Zhang J.
      • Xu J.
      • Xu G.
      • et al.
      Analysis of clinical features and outcomes of 161 patients with severe and critical COVID-19: a multicenter descriptive study.
      ,
      • Shi S.
      • Qin M.
      • Shen B.
      • Cai Y.
      • Liu T.
      • Yang F.
      • et al.
      Association of cardiac injury with mortality in hospitalized patients with COVID-19 in Wuhan, China.
      ,
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      • et al.
      Coronavirus disease 19 infection does not result in acute kidney injury: an analysis of 116 hospitalized patients from Wuhan, China.
      ,
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      ,
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      Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study.
      ,
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      ,
      • Zhang G.
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      • Luo L.
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      • Li J.
      • et al.
      Clinical features and short-term outcomes of 221 patients with COVID-19 in Wuhan, China.
      ,
      • Zhang X.
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      • Hu J.
      • Lian J.
      • Gu J.
      • Zhang S.
      • et al.
      Epidemiological, clinical characteristics of cases of SARS-CoV-2 infection with abnormal imaging findings.
      ,
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      • Yin H.
      • Hu Q.
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      • Tang Y.
      • et al.
      Clinical characteristics of patients with 2019 coronavirus disease in a non-Wuhan area of Hubei Province, China: a retrospective study.
      ,
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      Clinical characteristics of 34 COVID-19 patients admitted to intensive care unit in Hangzhou, China.
      ) and in 3852 out of 12 555 patients among eight studies outside Asia (
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      ). The pooled risk of AKI in Asia (10%, 95% CI 7–12%) was significantly lower than that outside Asia (35%, 95% CI 28–41%) (P < 0.00001).
      Compared with those who had non-severe COVID-19, patients with severe COVID-19 showed a significantly higher risk of developing AKI (13 studies, 7583 patients: RR 3.72, 95% CI 2.65–5.32, P < 0.00001; I2 = 79%; Figure 3A) (
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      Compassionate remdesivir treatment of severe Covid-19 pneumonia in intensive care unit (ICU) and non-ICU patients: clinical outcome and differences in post-treatment hospitalisation status.
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      Characterization and clinical course of 1000 patients with coronavirus disease 2019 in New York: retrospective case series.
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      Predictors for severe COVID-19 infection.
      ,
      • Cao J.
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      Clinical features and short-term outcomes of 18 patients with corona virus disease 2019 in intensive care unit.
      ,
      • Chen G.
      • Wu D.
      • Guo W.
      • Cao Y.
      • Huang D.
      • Wang H.
      • et al.
      Clinical and immunological features of severe and moderate coronavirus disease 2019.
      ,
      • Hirsch J.S.
      • Ng J.H.
      • Ross D.W.
      • Sharma P.
      • Shah H.H.
      • Barnett R.L.
      • et al.
      Acute kidney injury in patients hospitalized with COVID-19.
      ,
      • Hong K.S.
      • Lee K.H.
      • Chung J.H.
      • Shin K.
      • Choi E.Y.
      • Jin H.J.
      • et al.
      Clinical features and outcomes of 98 patients hospitalized with SARS-CoV-2 infection in Daegu, South Korea: a brief descriptive study.
      ,
      • Pei G.
      • Zhang Z.
      • Peng J.
      • Liu L.
      • Zhang C.
      • Yu C.
      • et al.
      Renal involvement and early prognosis in patients with COVID-19 pneumonia.
      ,
      • Yang Q.
      • Xie L.
      • Zhang W.
      • Zhao L.
      • Wu H.
      • Jiang J.
      • et al.
      Analysis of the clinical characteristics, drug treatments and prognoses of 136 patients with coronavirus disease 2019.
      ;
      • Zhang G.
      • Hu C.
      • Luo L.
      • Fang F.
      • Chen Y.
      • Li J.
      • et al.
      Clinical features and short-term outcomes of 221 patients with COVID-19 in Wuhan, China.
      ;
      • Zhao X.
      • Xu X.
      • Yin H.
      • Hu Q.
      • Xiong T.
      • Tang Y.
      • et al.
      Clinical characteristics of patients with 2019 coronavirus disease in a non-Wuhan area of Hubei Province, China: a retrospective study.
      ,
      • Zheng Y.
      • Sun L.
      • Xu M.
      • Pan J.
      • Zhang Y.
      • Fang X.
      • et al.
      Clinical characteristics of 34 COVID-19 patients admitted to intensive care unit in Hangzhou, China.
      ). Moreover, COVID non-survivors showed a statistically significant higher risk of developing AKI when compared to survivors (five studies, 6358 patients: RR 10.30, 95% CI 2.93–36.22, P < 0.00001; I2 = 76%; Figure 3B) (
      • Chen T.
      • Wu D.
      • Chen H.
      • Yan W.
      • Yang D.
      • Chen G.
      • et al.
      Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study.
      ,
      • Deng Y.
      • Liu W.
      • Liu K.
      • Fang Y.
      • Shang J.
      • Zhou L.
      • et al.
      Clinical characteristics of fatal and recovered cases of coronavirus disease 2019 (COVID-19) in Wuhan, China: a retrospective study.
      ,
      • Richardson S.
      • Hirsch J.S.
      • Narasimhan M.
      • Crawford J.M.
      • McGinn T.
      • Davidson K.W.
      • et al.
      Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area.
      ,
      • Wang L.
      • Li X.
      • Chen H.
      • Yan S.
      • Li D.
      • Li Y.
      • et al.
      Coronavirus disease 19 infection does not result in acute kidney injury: an analysis of 116 hospitalized patients from Wuhan, China.
      ,
      • Yang X.
      • Yu Y.
      • Xu J.
      • Shu H.
      • Xia J.
      • Liu H.
      • et al.
      Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study.
      ).
      Figure 3
      Figure 3Forest plots for the comparison of the risk of acute kidney injury (AKI) between two groups. (A) Comparison between patients with severe disease and those with non-severe disease for the risk of AKI. (B) Comparison between survivors and non-survivors for the risk of AKI. (Abbreviations: IV, inverse variance method; CI, confidence interval).
      Overall, 792 of 13 982 COVID-19 patients in 15 studies needed RRT (
      • Argenziano M.G.
      • Bruce S.L.
      • Slater C.L.
      • Tiao J.R.
      • Baldwin M.R.
      • Barr R.G.
      • et al.
      Characterization and clinical course of 1000 patients with coronavirus disease 2019 in New York: retrospective case series.
      ,
      • Cao J.
      • Hu X.
      • Cheng W.
      • Yu L.
      • Tu W.J.
      • Liu Q.
      Clinical features and short-term outcomes of 18 patients with corona virus disease 2019 in intensive care unit.
      ,
      • Chen T.
      • Wu D.
      • Chen H.
      • Yan W.
      • Yang D.
      • Chen G.
      • et al.
      Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study.
      ,
      • Cummings M.J.
      • Baldwin M.R.
      • Abrams D.
      • Jacobson S.D.
      • Meyer B.J.
      • Balough E.M.
      • et al.
      Epidemiology, clinical course, and outcomes of critically ill adults with COVID-19 in New York City: a prospective cohort study.
      ,
      • Hirsch J.S.
      • Ng J.H.
      • Ross D.W.
      • Sharma P.
      • Shah H.H.
      • Barnett R.L.
      • et al.
      Acute kidney injury in patients hospitalized with COVID-19.
      ,
      • Hong K.S.
      • Lee K.H.
      • Chung J.H.
      • Shin K.
      • Choi E.Y.
      • Jin H.J.
      • et al.
      Clinical features and outcomes of 98 patients hospitalized with SARS-CoV-2 infection in Daegu, South Korea: a brief descriptive study.
      ,
      • Malberti F.
      • Pecchini P.
      • Marchi G.
      • Foramitti M.
      When a nephrology ward becomes a COVID-19 ward: the Cremona experience.
      ,
      • Richardson S.
      • Hirsch J.S.
      • Narasimhan M.
      • Crawford J.M.
      • McGinn T.
      • Davidson K.W.
      • et al.
      Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area.
      ,
      • Shi M.
      • Chen L.
      • Yang Y.
      • Zhang J.
      • Xu J.
      • Xu G.
      • et al.
      Analysis of clinical features and outcomes of 161 patients with severe and critical COVID-19: a multicenter descriptive study.
      ,
      • Shi S.
      • Qin M.
      • Shen B.
      • Cai Y.
      • Liu T.
      • Yang F.
      • et al.
      Association of cardiac injury with mortality in hospitalized patients with COVID-19 in Wuhan, China.
      ,
      • Yang X.
      • Yu Y.
      • Xu J.
      • Shu H.
      • Xia J.
      • Liu H.
      • et al.
      Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study.
      ,
      • Yu Y.
      • Xu D.
      • Fu S.
      • Zhang J.
      • Yang X.
      • Xu L.
      • et al.
      Patients with COVID-19 in 19 ICUs in Wuhan, China: a cross-sectional study.
      ,
      • Zhang G.
      • Hu C.
      • Luo L.
      • Fang F.
      • Chen Y.
      • Li J.
      • et al.
      Clinical features and short-term outcomes of 221 patients with COVID-19 in Wuhan, China.
      ,
      • Zhao X.
      • Xu X.
      • Yin H.
      • Hu Q.
      • Xiong T.
      • Tang Y.
      • et al.
      Clinical characteristics of patients with 2019 coronavirus disease in a non-Wuhan area of Hubei Province, China: a retrospective study.
      ,
      • Zheng Y.
      • Sun L.
      • Xu M.
      • Pan J.
      • Zhang Y.
      • Fang X.
      • et al.
      Clinical characteristics of 34 COVID-19 patients admitted to intensive care unit in Hangzhou, China.
      ), and the pooled requirement for RRT was 7% (95% CI 5–9%, I2 = 96%) (Figure 4). Non-severe COVID-19 patients showed a significantly lower risk of RRT than severe COVID-19 patients (seven studies, 6845 patients: RR 0.06, 95% CI 0.02–0.25, P < 0.00001; I2 = 89%; Figure 5A) (
      • Argenziano M.G.
      • Bruce S.L.
      • Slater C.L.
      • Tiao J.R.
      • Baldwin M.R.
      • Barr R.G.
      • et al.
      Characterization and clinical course of 1000 patients with coronavirus disease 2019 in New York: retrospective case series.
      ,
      • Cao J.
      • Hu X.
      • Cheng W.
      • Yu L.
      • Tu W.J.
      • Liu Q.
      Clinical features and short-term outcomes of 18 patients with corona virus disease 2019 in intensive care unit.
      ,
      • Hirsch J.S.
      • Ng J.H.
      • Ross D.W.
      • Sharma P.
      • Shah H.H.
      • Barnett R.L.
      • et al.
      Acute kidney injury in patients hospitalized with COVID-19.
      ,
      • Hong K.S.
      • Lee K.H.
      • Chung J.H.
      • Shin K.
      • Choi E.Y.
      • Jin H.J.
      • et al.
      Clinical features and outcomes of 98 patients hospitalized with SARS-CoV-2 infection in Daegu, South Korea: a brief descriptive study.
      ,
      • Zhang G.
      • Hu C.
      • Luo L.
      • Fang F.
      • Chen Y.
      • Li J.
      • et al.
      Clinical features and short-term outcomes of 221 patients with COVID-19 in Wuhan, China.
      ,
      • Zhao X.
      • Xu X.
      • Yin H.
      • Hu Q.
      • Xiong T.
      • Tang Y.
      • et al.
      Clinical characteristics of patients with 2019 coronavirus disease in a non-Wuhan area of Hubei Province, China: a retrospective study.
      ,
      • Zheng Y.
      • Sun L.
      • Xu M.
      • Pan J.
      • Zhang Y.
      • Fang X.
      • et al.
      Clinical characteristics of 34 COVID-19 patients admitted to intensive care unit in Hangzhou, China.
      ). In addition, RRT was less frequently required in COVID-19 survivors when compared to non-survivors (three studies, 6026 patients: RR 0.20, 95% CI 0.16–0.26, P < 0.00001; I2 = 0%; Figure 5B) (
      • Chen T.
      • Wu D.
      • Chen H.
      • Yan W.
      • Yang D.
      • Chen G.
      • et al.
      Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study.
      ,
      • Richardson S.
      • Hirsch J.S.
      • Narasimhan M.
      • Crawford J.M.
      • McGinn T.
      • Davidson K.W.
      • et al.
      Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area.
      ,
      • Yang X.
      • Yu Y.
      • Xu J.
      • Shu H.
      • Xia J.
      • Liu H.
      • et al.
      Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study.
      ).
      Figure 4
      Figure 4Forest plot of the overall requirement for renal replacement therapy. (Abbreviations: SE, standard error; IV, inverse variance method; CI, confidence interval).
      Figure 5
      Figure 5Forest plots for the comparison of the requirement for renal replacement therapy (RRT) between two groups. (A) Comparison between patients with severe disease and those with non-severe disease for the requirement for RRT. (B) Comparison between survivors and non-survivors for the requirement for RRT. (Abbreviations: IV, inverse variance method; CI, confidence interval).
      Significant publication bias was noticed on the basis of the funnel plot for AKI (Supplementary material Figure S1) but not for RRT (Supplementary material Figure S2).

      Discussion

      Main findings

      This study provides a comprehensive overview of the available evidence on the spatiotemporal trend of renal involvement in COVID-19. A total of 17 134 patients in 30 studies from four countries were included. The analysis revealed that the overall risk of AKI in COVID-19 patients was 19%, with a significant spatiotemporal difference. Moreover, patients with AKI, similar to patients who needed RRT, were found to be more likely to become seriously ill or even to die.

      Interpretation

      SARS-CoV-2 has caused the third coronavirus epidemic in the third millennium, after SARS-CoV and MERS-CoV (
      • Čivljak R.
      • Markotić A.
      • Kuzman I.
      The third coronavirus epidemic in the third millennium: what’s next?.
      ). Coronaviruses, which belong to the family Coronaviridae, are a large group of RNA viruses named after their spiky structure that looks a bit like a corona, or crown (
      • González J.M.
      • Gomez-Puertas P.
      • Cavanagh D.
      • Gorbalenya A.E.
      • Enjuanes L.A.
      Comparative sequence analysis to revise the current taxonomy of the family Coronaviridae.
      ). Like other coronaviruses, SARS-CoV-2 is spherical with spike proteins, which allow the coronavirus to attach to cells that it can invade. Once a virus enters the human body through the eyes, mouth, or nose, it seeks cells with its favorite doorways—proteins called receptors. If the virus finds a compatible receptor, it can invade and start replicating itself. For SARS-CoV-2, this receptor is found across the entire body (
      • Hirano T.
      • Murakami M.
      COVID-19: a new virus, but a familiar receptor and cytokine release syndrome.
      ).
      The attachment of SARS-CoV-2 spike protein to angiotensin‐converting enzyme 2 (ACE2), the cellular receptor, can promote the invasion, replication, and intercellular transmission of the virus (
      • Hirano T.
      • Murakami M.
      COVID-19: a new virus, but a familiar receptor and cytokine release syndrome.
      ). Although there has been no evidence of glomerular involvement, immunohistochemistry has indicated that the SARS-CoV-2 nucleoprotein antigen is overexpressed in the tubular cells, and this is accompanied by severe acute tubular necrosis (
      • Puelles V.G.
      • Lutgehetmann M.
      • Lindenmeyer M.T.
      • Sperhake J.P.
      • Wong M.N.
      • Allweiss L.
      • et al.
      Multiorgan and renal tropism of SARS-CoV-2.
      ). The biomolecular interactions between SARS-CoV-2 and ACE2 expressed in kidneys are considered to lead to the inevitable process of AKI in patients infected with this virus. On the other hand, immune-mediated disorders of the kidney could be one possible explanation for AKI in COVID-19. SARS-CoV-2 infection will result in disturbances of T1 and T2 immune responses (
      • Hoiland R.L.
      • Stukas S.
      • Cooper J.
      • Thiara S.
      • Chen L.
      • Biggs C.M.
      • et al.
      Amelioration of COVID-19 related cytokine storm syndrome: parallels to chimeric antigen receptor-T cell cytokine release syndrome.
      ), contributing to an increase in the levels of cytokines and chemokines including interleukin 4 (IL-4), interleukin 6 (IL-6), and interferon-inducible protein 10 (IP-10) (
      • Hirano T.
      • Murakami M.
      COVID-19: a new virus, but a familiar receptor and cytokine release syndrome.
      ). In addition, the toxicity of drugs might lead to AKI patients suffering from novel coronavirus pneumonia, based on the fact that pharmacotherapy is the key approach to manage it (
      • Peng F.
      • Tu L.
      • Yang Y.
      • Hu P.
      • Wang R.
      • Hu Q.
      • et al.
      Management and treatment of COVID-19: the Chinese experience.
      ).
      A surprising finding of this study was that the risk of AKI in patients with confirmed COVID-19 did not show a downward trend over time as expected. Instead, the subgroup analysis, according to the patient enrollment period, showed that the overall risk of AKI in patients enrolled after March 1, 2020 (36%) was higher than that in patients enrolled before March 1, 2020 (9%). The mutation of SARS-CoV-2 might have played a role in this finding. SARS-CoV-2 is an RNA virus with a high mutation rate, which can contribute to transmission and virulence. A recent study (
      • Hu J.
      • He C.
      • Gao Q.
      • Zhang G.
      • Cao X.
      • Long Q.
      • et al.
      The D614G mutation of SARS-CoV-2 spike protein enhances viral infectivity and decreases neutralization sensitivity to individual convalescent sera.
      ) that elaborated the dominant mutation of SARS-CoV-2 at position 614 of the spike protein (D614G mutation), reported that the proportion of the D614G strain in all SARS-CoV-2 increased from 0 in early 2020 to 70% in May 2020, indicating that the mutant strain had become the dominant strain globally. Moreover, Choe et al. found that the D614G mutation in SARS-CoV-2 could increase the number of spike proteins and facilitate viral invasion (
      • Zhang L.
      • Jackson C.B.
      • Mou H.
      • Ojha A.
      • Rangarajan E.S.
      • Izard T.
      • et al.
      The D614G mutation in the SARS-CoV-2 spike protein reduces S1 shedding and increases infectivity.
      ). During the present study, it was found that patients enrolled before March 1, 2020 were from Asia. Therefore, a further subgroup analysis based on location was performed.
      Generally, there was less AKI in patients in Asia (10%) compared to patients outside Asia (35%). Given that the vast majority of the population in Italy and the United States are Caucasian, the study findings may be inextricably bound up with ethnic differences in the frequency of variants in ACE2, the cellular receptor of SARS-CoV-2. ACE2 variants, which are determined by genes, have been known to differ in frequency among populations (
      • Cao Y.
      • Li L.
      • Feng Z.
      • Wan S.
      • Huang P.
      • Sun X.
      • et al.
      Comparative genetic analysis of the novel coronavirus (2019-nCoV/SARS-CoV-2) receptor ACE2 in different populations.
      ,
      • Strafella C.
      • Caputo V.
      • Termine A.
      • Barati S.
      • Gambardella S.
      • Borgiani P.
      • et al.
      Analysis of ACE2 genetic variability among populations highlights a possible link with COVID-19-related neurological complications.
      ). The virus might attach to receptors with higher affinity, if more ACE2 gene variants are expressed in the epithelial cells of the renal tubule among Caucasians. On the other hand, these ACE2 variants may be less expressed in Asians, who less frequently presented AKI among these COVID-19 patients. Moreover, it could be inferred that evident cultural differences also play an important role in the different risk between Caucasians and Asians, such as attitudes towards wearing a facemask, keeping a safe social distance, and strategies of containment.

      Limitations

      This study had some limitations. Firstly, as described above, the heterogeneity among the studies included was high, and publication bias was noticed for several outcomes. Therefore, caution should be taken when drawing conclusions, although heterogeneity was accounted for by using a random-effects model and performing subgroup analyses. Secondly, the definition of AKI was not uniform across all included studies; however, the KDIGO criteria were applied in most studies to define AKI. Nevertheless, we could not perform further investigations, due to the lack of information pertaining to the definition of AKI in some studies. Thirdly, the renal function indexes, including serum creatinine, blood urea nitrogen, endogenous creatinine clearance rate, and estimated glomerular filtration rate, were not evaluated, as the raw data in the 30 studies were too scarce to conduct meta-analyses.

      Conclusions

      In conclusion, this study is novel in presenting an estimation of the spatiotemporal trend of renal involvement in COVID-19, which may act as a sign of deterioration. This study revealed that COVID-19 patients enrolled after March 1, 2020 had a higher risk of renal involvement than those enrolled before March 1, 2020. Also, compared to patients outside Asia, those in Asia had a lower risk of renal involvement. Constant vigilance and effort are required to manage these patients.

      Funding

      This work was supported by Zhejiang Medical and Health Science and Technology Program, China (2017KY711), the General Projects of Social Development of Taizhou City, China (1701KY36), and theProject of Taizhou Central Hospital, China (2019KT003).

      Ethical approval and consent to participate

      Not applicable.

      Conflict of interest

      The authors have no conflicts of interest to disclose.

      Author contributions

      YFF and KPW performed the literature search, screened for relevant studies, extracted data; JGM, YHX, LZW, and CJ analyzed the data, interpreted the results, and drafted the manuscript; XC and BY contributed equally as co-corresponding authors, conceived and designed the research, revised the manuscript, and offered suggestions. All authors approved the final version of the manuscript.

      Acknowledgements

      We appreciate the work of the authors of the 30 studies included, and all reviewers and editors for reviewing this work.

      Appendix A. Supplementary data

      The following are Supplementary data to this article:

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