key: cord-0823224-dobqll92 authors: Liu, Y.-F.; Zhang, Z.; Pan, X.-L.; Xing, G.-L.; Zhang, Y.; Liu, Z.-S.; Tu, S.-H. title: The Chronic Kidney Disease and Acute Kidney Injury Involvement in COVID-19 Pandemic: A Systematic Review and Meta-analysis date: 2020-05-02 journal: nan DOI: 10.1101/2020.04.28.20083113 sha: dddbd650094f9a9706774da381d7cdc2bbcb967a doc_id: 823224 cord_uid: dobqll92 Aim: The aim of this study was to uncover whether kidney diseases were involved in COVID-19 pandemic from a systematic review. Methods: The studies reported the kidney outcomes in different severity of COVID-19 were included in this study. Standardized mean differences or odds ratios were calculated by employing Review Manager meta-analysis software. Results: Thirty-six trials were included in this systematic review with a total of 6395 COVID-19 patients. The overall effects indicated that the comorbidity of chronic kidney disease (CKD) (OR = 3.28), complication of acute kidney injury (AKI) (OR = 11.02), serum creatinine (SMD = 0.68), abnormal serum creatinine (OR = 4.86), blood urea nitrogen (SMD = 1.95), abnormal blood urea nitrogen (OR = 6.53), received continuous renal replacement therapy (CRRT) (OR = 23.63) was significantly increased in severe group than that in nonsevere group. Additionally, the complication of AKI (OR = 13.92) and blood urea nitrogen (SMD = 1.18) were remarkably elevated in critical group than that in severe group. Conclusion: CKD and AKI are susceptible to occur in patients with severe COVID-19. CRRT is applied frequently in severe COVID-19 patients than that in nonsevere COVID-19 patients. The risk of AKI is higher in critical group than that in severe group. sequencing, direct PCR, and culture [2] . The next-generation sequencing of 2019-nCoV confirmed that it is sufficiently divergent from severe acute respiratory syndrome (SARS)-CoV and considered as a novel human-infecting betacoronavirus [3] . Moreover, structural analysis revealed that 2019-nCoV might bind to the angiotensin converting enzyme 2 (ACE2) receptor in humans [3] . 2020, a total of more than 1,848,000 laboratory-confirmed cases had been documented worldwide. The most common clinical characteristics were fever (43.8% on admission and 88.7% during hospitalization) and cough (67.8%) [4] . The single-cell RNA sequencing datasets indicated that ACE2 was mainly expressed in lung type II alveolar cells, colon colonocytes, ileum ECs, and proximal tubule cells [5, 6] . In addition, SARS-CoV-2 was detected in urine, blood, anal swab, and oropharyngeal swab from nine patients with COVID-19 who were retested by qRT-PCR [7] . The above evidence revealed that SARS-CoV-2 can affect respiratory system, digestive system, hematological system, and urinary system which were associated with the clinical features of COVID-19. Moreover, the single-cell transcriptome analysis identified that ACE2 and transmembrane protease serine 2 (TMPRSS2) genes are relatively high coexpression in podocytes and proximal tubule cells [8] . selection has been drafted in accordance to the PRISMA principle. 2.3. Data Extraction and Management. The data were extracted by two independent reviewers (XL Pan and GL Xing), and contradictions were resolved by consensus or were judged by another author. The data presented as median and interquartile range was transformed into mean and standard deviation according to the formula below (http://www.math.hkbu.edu.hk/~tongt/papers/median2mean.html). The studies' quality was evaluated according to the Newcastle-Ottawa scale (NOS) which assess the quality of nonrandomised studies in meta-analyses [14] . The quality of the included studies was estimated independently by two investigators (SH studies [1, 4, . In 8 studies, the COVID-19 patients were classified as more than two groups according to the disease severity which included severe and critical . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted May 2, 2020. . https://doi.org/10.1101/2020.04. 28.20083113 doi: medRxiv preprint COVID-19 patients [41] [42] [43] [44] [45] [46] [47] [48] . Finally, 36 studies were included in the study. The characteristics of the studies were indicated in Table 1. Together, 6395 COVID-19 patients were included in the study. 3.2. Study Descriptions. All the included studies were performed in China. Five studies were published in Chinese [30] [31] [32] 47, 48] , and the others were published in English. Eight studies were conducted as multi-center trials [4, 15, 19, [23] [24] [25] 29, 45] . The patients with COVID-19 divided into ICU care and no ICU care in four studies were included in the severe and nonsevere groups [1, 36, 37, 39] . The COVID-19 patients divided into ARDS (acute respiratory distress syndrome) and non-ARDS in one study were also included in the severe and nonsevere groups [38] . Two studies combined the data of severe and critical patients together, and they were also included in subgroup severe and nonsevere groups [30, 31] . Table 1 , the majority of included studies were poor quality except four studies whose NOS scores are 6 [1, 16, 31, 43] . The NOS scores of other 31 trials are 5, and only one trial's NOS scores were 4. 3.4. Publication Bias. As the included studies of three outcomes > 10 in severe and nonsevere groups, the funnel plots were conducted to estimate the publication bias ( Fig. 2) . The funnel plot of CKD was symmetrical, suggesting that there was no publication bias. However, the funnel plot of blood urea nitrogen was a little asymmetrical, implying that the publication bias existed to some extent. CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted May 2, 2020. . https://doi.org/10.1101/2020.04. 28.20083113 doi: medRxiv preprint the studies (P = 0.12). Eight studies reported complication of AKI (involving 2072 subjects), and complication of AKI was significantly elevated in severe group than that in nonsevere group (P < 0.00001, OR = 11.02, 95% CI: 6.54 to 18.57). 3.5.1.3. The outcome of serum creatinine. As illustrated in Fig. 3 , the number of participants ranged from 21 to 564. There was statistical heterogeneity between the studies (P < 0.00001). Twenty-two studies measured serum creatinine (including 3261 subjects), and pooled results showed that serum creatinine was remarkably increased in severe group than that in nonsevere group (P = 0.0005, SMD = 0.68, 95% CI: 0.3 to 1.06). 3.5.1.4. The outcome of abnormal serum creatinine. As indicated in Fig. 3 , the number of participants ranged from 77 to 752. There was no statistical heterogeneity between the studies (P = 0.51). Seven studies documented abnormal serum creatinine (including 1775 subjects), and severe group had a higher ratio of abnormal serum creatinine than nonsevere group (P < 0.00001, OR = 4.86, 95% CI: 2.71 to 8.7). 3.5.1.5. The outcome of blood urea nitrogen. As illustrated in Fig. 3 , the number of participants ranged from 21 to 564. There was statistical heterogeneity between the studies (P < 0.00001). Seventeen studies assayed blood urea nitrogen (including 2814 subjects), and pooled results revealed that blood urea nitrogen was significantly elevated in severe group than that in nonsevere group (P < 0.00001, SMD = 1.95, 95% CI: 1.23 to 2.66). 3.5.1.6. The outcome of abnormal blood urea nitrogen. As showed in Fig. 3 , the number of participants ranged from 122 to 193. There was no statistical heterogeneity between the studies (P = 0.67). Four studies documented abnormal blood urea nitrogen (involving 683 subjects), and severe group had a higher ratio of abnormal blood urea nitrogen than nonsevere group (P < 0.00001, OR = 6.53, 95% CI: 3.42 to 12.46). 3.5.1.7. The outcome of receiving CRRT. As illustrated in Fig. 3 , the number of participants ranged from 41 to 1099. There was no statistical heterogeneity between the studies (P = 0.84). Six studies reported receiving CRRT (including 1827 subjects), and severe group had higher ratio of receiving CRRT than nonsevere group (P < . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 2, 2020. Only one study reported abnormal blood urea nitrogen and abnormal serum creatinine, so the result was not pooled. CRRT was not documented in this subgroup. To our knowledge, this is the first research which comprehensively illustrates the kidney involvement in COVID-19 pandemic. This systematic review observed that the CKD and AKI were involved in the COVID-19. Compared with nonsevere group, . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 2, 2020. . https://doi.org/10.1101/2020.04. 28.20083113 doi: medRxiv preprint the comorbidity of CKD (OR = 3.28) and complication of AKI (OR = 11.02) were significantly elevated in severe group. Meanwhile, AKI occurred in 4.3% COVID-19 patients, and 21.1% were severe COVID-19 patients. The complication of AKI is lower than 5.1% which was reported in a previous cohort study, of which 42.7% were severely ill [9] . The different disease severity and sample size may contribute to the difference. The comorbidity of CKD is similar to previous meta-analysis (including 1389 participants) which showed that CKD was significantly associated with severe COVID-19 (OR = 3.03), among which 19.7% were defined as severe COVID-19 [10] . Furthermore, the serum creatinine, ratio of abnormal serum creatinine, blood urea nitrogen, ratio of abnormal blood urea nitrogen were remarkably elevated in severe group than that in nonsevere group, with SMD = 0.68, OR = 4.86, SMD = 1.95, OR = 6.53, respectively. The OR regarding abnormal serum creatinine and abnormal blood urea nitrogen were lower than that in the severe and nonsevere groups with regard to AKI. The AKI also occurred in normal serum creatinine and blood urea nitrogen, which could lead to the higher OR of AKI. The CRRT is recommended in severe or critical patients because it reduces cytokine damage, removes endotoxin, and improves cardiac function and kidney function [49] . Hence, the severe group had higher ratio of receiving CRRT than nonsevere group (OR = 23.63). The critical group had a higher ratio of AKI than that in severe group (OR = 13.92) which is higher than subgroup severe and nonsevere groups (OR = 11.02). Furthermore, the blood urea nitrogen was increased in critical group than that in severe group (SMD = 1.18). However, there is no significant difference between the two groups with regard to comorbidity of CKD. Owing to immunodepression of CKD, cytokine storm is weakened and CKD patients are not vulnerable to critical COVID-19, which could explain the result. Meanwhile, there was no significant increase in serum creatinine in critical group. We speculated that the CRRT was frequently applied in critical group, so the serum creatinine was not notably elevated in critical group. In addition, AKI is diagnosed not only by abnormal serum creatinine but also the change of serum creatinine and urine volume. . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 2, 2020. . https://doi.org/10.1101/2020.04. 28.20083113 doi: medRxiv preprint There are lots of reasons which give rise to the kidney impairment in COVID-19. First, SARS-CoV-2 viral load induce cytotoxicity of renal resident cells. The endothelial cell swelling, renal tubular epithelial cell swelling, vacuolar degeneration, and drop were observed with light microscope of renal biopsy in three COVID-19 cases [50] . Second, the fever, vomit, diarrhea, and shock are likely to cause kidney hypoperfusion. Third, Serum SARS-CoV-2 viral load (RNAaemia) is strongly associated with cytokine storm [43] . cytokine storm participated in SARS-CoV-2 infection [51] . A renal transplanted patient with COVID-19 showed a mild disease because immunosuppression of renal transplantation can "be protective" [52] . Fourth, the nephrotoxicity of some drugs, such as non-steroidal anti-inflammatory drugs, antivirals, antibiotics, and antifungal could lead to kidney damage. Fifth, organ crosstalk such as cardiorenal syndrome, hypoxia, and rhabdomyolysis also could cause kidney impairment [49] . Sixth, mechanical ventilation is able to result in AKI [53] . Seventh, the elderly patients with comorbidities such as hypertension, diabetes, chronic cardiology disease, or chronic liver disease are susceptible to trigger secondary kidney diseases which may not be confirmed before admission. Several limitations of the included studies should be concerned. First, all the included studies did not stage CKD. Different CKD stage could have different risks for COVID-19 and have different prognosis. Second, only one study [9] reported the AKI stage which reflects the AKI severity, progression, and prognosis. AKI occurred primarily or AKI on CKD is unknown for the included studies. Third, all the included studies did not qualify the 24h total urine protein. Therefore, it is difficult to judge the severity of potential kidney diseases. Fourth, all the included studies did not measure the 24h urine volume or the change of urine volume which is beneficial for the diagnosis of AKI. Only two studies reported the urine routine [15, 39] . Finally, the outcomes of AKI were unclear. Several limitations of this study should be noticed. First, all the included trials were conducted in Chinese populations, which inferred a high risk of selection bias. Second, most of the studies were of poor quality except four studies. Third, the heterogeneity was significant in terms of serum creatinine and blood urea nitrogen. . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 2, 2020. . https://doi.org/10.1101/2020.04. 28.20083113 doi: medRxiv preprint The different disease severity, different sample size, different detection methods, and reference range were responsible for the heterogeneity. Fourth, the children or teenagers COVID-19 patients were probably included in this study because the included studies did not clearly restrict to adult COVID-19 patients. Fifth, the quality of the most of included studies was low which may weaken the evidence level. Finally, the most important criteria eGFR was reported in only three studies [30, 37, 47] . In view of this, we should carefully interpret all of the conclusions due to the considerable poor quality and clinical variety of the studies. In conclusion, this systematic review suggests that CKD and AKI are involved in severe COVID-19. Severe COVID-19 is susceptible to occur in CKD patients than nonsevere COVID-19. With the severity of COVID-19 increasing, the risk of AKI elevated strikingly. CRRT is applied more frequently in severe group than that in nonsevere group. Clinicians should be cautious of kidney diseases in patients with COVID-19, especially the severe and critical COVID-19. More attention should be paid to monitoring kidney function to avoid end stage renal disease and decease in COVID-19 pandemic. . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 2, 2020. . https://doi.org/10.1101/2020.04. 28.20083113 doi: medRxiv preprint Funding This work was funded by the National Natural Science Foundation of China (81701601). All authors state that there is no conflict of interest. We would like to acknowledgement the National Natural Science Foundation of China for its financial support. The data used to support the findings of this study are available from the corresponding author upon request. . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 2, 2020. . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 2, 2020. . https://doi.org/10.1101/2020.04. 28.20083113 doi: medRxiv preprint Fig. 1 . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 2, 2020. . is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted May 2, 2020. . https://doi.org/10.1101/2020.04. 28.20083113 doi: medRxiv preprint . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted May 2, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted May 2, 2020. . https://doi.org/10.1101/2020.04. 28.20083113 doi: medRxiv preprint Abnormal serum creatinine Blood urea nitrogen Abnormal blood urea nitrogen CRRT . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted May 2, 2020. . https://doi.org/10.1101/2020.04. 28.20083113 doi: medRxiv preprint . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted May 2, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted May 2, 2020. . https://doi.org/10.1101/2020.04. 28.20083113 doi: medRxiv preprint Clinical features of patients infected with 2019 novel coronavirus in Wuhan A Novel Coronavirus from Patients with Pneumonia in China Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding Clinical Characteristics of Coronavirus Disease 2019 in China Single cell RNA sequencing of 13 human tissues identify cell types and receptors of human coronaviruses. Biochemical and biophysical research communications Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019-nCoV infection. Frontiers of medicine Novel Coronavirus can be detected in urine, blood, anal swabs and oropharyngeal swabs samples. medRxiv Identification of a potential mechanism of acute kidney injury during the COVID-19 outbr eak: a study based on single-cell transcriptome analysis Kidney disease is associated with in-hospital death of patients with COVID-19 Chronic kidney disease is associated with severe coronavirus disease 2019 (COVID-19) infection. International urology and nephrology Diagnosis and treatment of COVID-19: acute kidney injury cannot be ignored Coronavirus Disease 19 Infection Does Not Result in Acute Kidney In jury: Controls in Chinese Han Population. medRxiv Clinical features and laboratory inspection of novel coronavirus pneumonia (COVID-19) in Xiangyang Clinical features and outcomes of 221 patients with COVID -19 in Wuhan Clinical characteristi cs of 51 patients discharged from hospital with COVID-19 in Chongqing，China. medRxiv Epidemiologic and Clinical Characteristics of 91 Hospitalized Patients with COVID-19 in Zhejiang, China: A retrospective, multi -centre case series. medRxiv Epidemiological and clinical features of 2019 -nCoV acute respiratory disease cases in Chongqing municipality Neutrophil -to-Lymphocyte Ratio Predicts Severe Illness Patients with 2019 Novel Coronavirus in the Early Stage. medRxiv Potential biochemi cal markers to identify severe cases among COVID-19 patients. medRxiv Prognostic factors for COVID-19 pneumonia progression to severe symptom based on the earlier clinical features: a retrospective analysis. medRxiv The Use of Adjuvant Therapy in Preventing Progression to Severe Pneumonia in Patients with Coronavirus Disease 2019: A Multicenter Data Analysis. medRxiv Clinical characteristics and treatment strategies of 79 patients with COVID-19 Clinical Features of Patients Infected with the 2019 Novel Coronavirus (COVID-19 Proteomic and Metabolomic Characterization of COVID-19 Acute kidney injury at early stage as a negative prognostic indicator of patients with COVID-19: a hospital-based retrospective analysis. medRxiv Blood glucose is a representative of the clustered indicators of multi-organ injury for predicting mortality of COVID-19 in Wuhan Detectable serum SARS-CoV-2 viral load (RNAaemia) is closely associated with drastically elevated interleukin 6 (IL-6) level in critically ill COVID-19 patients. medRxiv Risk Factors Associated with Clinical Outcomes COVID-19 with Different Severity: A Multi -center Study of Clinical Features. American journal of respiratory and critical care medicine Clinical and radiographic features of cardiac injury in patients with 2019 novel coronavirus pneumonia. medRxiv Clinical characteristic of 90 patients with COVID-19 hospitalized in a Grade-A hospital in Beijing Clinical characteristics, treatment, and prognosis in 89 cases of COVID-2019 Kidney involvement in COVID-19 and rationale for extracorporeal therapies