If you don't remember your password, you can reset it by entering your email address and clicking the Reset Password button. You will then receive an email that contains a secure link for resetting your password
If the address matches a valid account an email will be sent to __email__ with instructions for resetting your password
Department of Anesthesia, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510655, ChinaDepartment of Anesthesiology, Xiangya Hospital, Central South University, Changsha 410008, ChinaDepartment of Hepatobiliary and Pancreatic Surgery, The Third Xiangya Hospital, Central South University, Changsha 410013, China
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.
Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha 410008, ChinaDepartment of Cardiothoracic Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China
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.
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 (
). 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 (
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 (
). 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 (
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.
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 (
). 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 (
), 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 (
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 (
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 (
). 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 (
). 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 (
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 (
Clinical features, laboratory characteristics, and outcomes of patients hospitalized with coronavirus disease 2019 (COVID-19): early report from the United States.
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.
Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study.
Overall, the 30 studies included 17 134 patients. Thirteen studies described the prevalence of AKI in patients with severe versus non-severe COVID-19 (
Clinical features, laboratory characteristics, and outcomes of patients hospitalized with coronavirus disease 2019 (COVID-19): early report from the United States.
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.
Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study.
Remote ischaemic preconditioning reduces acute kidney injury in adult patients undergoing cardiac surgery with cardiopulmonary bypass: a meta-analysis.
Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study.
Clinical features, laboratory characteristics, and outcomes of patients hospitalized with coronavirus disease 2019 (COVID-19): early report from the United States.
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.
Clinical features, laboratory characteristics, and outcomes of patients hospitalized with coronavirus disease 2019 (COVID-19): early report from the United States.
Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study.
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.
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 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 (
Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study.
Clinical features, laboratory characteristics, and outcomes of patients hospitalized with coronavirus disease 2019 (COVID-19): early report from the United States.
). 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.
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 (
Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study.
Clinical features, laboratory characteristics, and outcomes of patients hospitalized with coronavirus disease 2019 (COVID-19): early report from the United States.
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.
). 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) (
Clinical features, laboratory characteristics, and outcomes of patients hospitalized with coronavirus disease 2019 (COVID-19): early report from the United States.
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.
). 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) (
Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study.
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).
Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study.
), 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) (
). 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) (
Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study.
Figure 4Forest plot of the overall requirement for renal replacement therapy. (Abbreviations: SE, standard error; IV, inverse variance method; CI, confidence interval).
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 (
). 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 (
). 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 (
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 (
). 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 (
). 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 (
), 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) (
). 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 (
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 (
) 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 (
). 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 (
). 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:
Funnel plot of standard error by the log of the risk difference for renal replacement therapy. (Abbreviations: SE, standard error; RD, risk difference).
References
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.
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.
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.
Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study.
Remote ischaemic preconditioning reduces acute kidney injury in adult patients undergoing cardiac surgery with cardiopulmonary bypass: a meta-analysis.
00300-3&id=gr1.jpg){kind=link}
00300-3&id=gr2.jpg){kind=link}
00300-3&id=gr3.jpg){kind=link}
00300-3&id=gr4.jpg){kind=link}
00300-3&id=gr5.jpg){kind=link}