key: cord-265877-dund6unq authors: Yang, Q.; Yang, X. title: Incidence and risk factors of kidney impairment on patients with COVID-19: a systematic review and meta-analysis date: 2020-06-03 journal: nan DOI: 10.1101/2020.05.28.20116400 sha: doc_id: 265877 cord_uid: dund6unq Background: The novel coronavirus is pandemic around the world. Several researchers have given the evidence of impacts of COVID-19 on the respiratory, cardiovascular and gastrointestinal system. Studies still have debated on kidney injury of COVID-19 patients. The purpose of the meta-analysis was to evaluate the association of kidney impairment with the development of COVID-19. Methods: The PubMed, Embase and MedRxiv databases were searched until April 1, 2020. We extracted data from eligible studies to summarize the clinical manifestations and laboratory indexes of kidney injury on COVID-19 infection patients and further compared the prevalence of acute kidney injury (AKI) and the mean differences of three biomarkers between in ICU/severe and non-ICU/non-severe cases. Heterogeneity was evaluated using the I2 method. Results: In the sum of 19 studies with 4375 patients were included in this analysis. The pooled prevalence of AKI, increased serum creatinine (Scr), increased blood urea nitrogen (BUN), increased D-dimer, proteinuria and hematuria in patients with COVID-19 were 7.7%, 6.6%, 6.2%, 49.8%, 42% and 30.3% respectively. Moreover, the means of Scr, BUN and D-dimer were shown 6-folds, 1.8-folds and 0.68-folds, respectively, higher in ICU/severe cases than in corresponding non-ICU/non-severe patients. The prevalence of AKI was about 17 folds higher in ICU/severe patients compared with the non-ICU/non-severe cases. Conclusions: Overall, we assessed the incidences of the clinic and laboratory features of kidney injury in COVID-19 patients. And kidney dysfunction may be a risk factor for COVID-19 patients developing into the severe condition. In reverse, COVID-19 can also cause damage to the kidney. In December 2019, a group of pneumonia cases caused by an unknown virus was first reported in Wuhan, Hubei province, China 1,2 . Those cases have similar symptoms of virus infection, including fever, fatigue, and dry cough as well as myalgia, dyspnea 1, 2 . WHO has officially named this novel coronavirus as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) after the pathogen was isolated and identificated 3, 4 . Nowadays, this novel coronavirus is causing COVID-19 epidemic on the international scale due to its highly transmissive and contagiousness, compared with other coronavirus infection diseases including Middle East Respiratory Syndrome (MERS) and Severe Acute Respiratory Syndrome (SARS) 5 . As of April 21, 2020, a total of 2531804 confirmed cases involved in 185 countries and regions, and the numbers continue to rise. And SARS-CoV-2 mainly causes a series of the clinical characteristics in the respiratory system, such as asymptomatic infection, mild upper respiratory tract illness, severe acute respiratory distress syndrome, respiratory failure and even death 1,2,6 . The pathogenic mechanism of SARS-CoV-2 is binding to membrane ACE2 for entering into pulmonary cells 4 . And ACE2 is widely distributing in several vital organs including lung, heart, kidney and intestine 7 . Apart from the respiratory symptom, SARS-CoV-2 also caused cardiovascular damage, not only led to acute cardiac injury (ACI) with an increased highsensitivity cardiac troponin I (hs-cTnI) in clinic 1 . On the other hands, patients with pre-existing cardiovascular diseases (CVDs) are more likely developed into the severe condition and even contribute to highly mortality 1, 8, 9 . Moreover, SARS-CoV-2 has an impact on the gastrointestinal system, bringing symptom like diarrhea with a statistically significant difference, which may be underestimated on clinical diagnosis 10 . Further study has proved that SARS-CoV-2 infects the gastrointestinal tract, the results of histologic and immunofluorescent staining of gastrointestinal tissues from COVID-19 patients were showed that the existence of ACE2 receptor and viral nucleocapsid protein in the cytoplasm of gastric, duodenal, and rectum glandular epithelial cell. 11 Therefore, we are also concerned whether SARS-CoV-2 causes kidney dysfunction and whether COVID-19 patients with kidney impairment are at a higher risk. Some clinical studies have focus attention on kidney injury of COVID-19 patients. Zhen Li et al. has shown that a large proportion of COVID-19 patients is accompanied by kidney dysfunction, including proteinuria, hematuria, increased serum creatine and blood urea nitrogen 12 . Yichun Cheng also demonstrated that kidney injury is associated with in-hospital death of COVID-19 patients 13 . However, Luwen Wang thought that SARS-CoV-2 did not cause obviously kidney damage to patients 14 . With issue arising, a meta-analysis with large clinical samples is desperately warranted to produce a convincible result. Meta-Analyses of individual participant data (the PRISMA-IPD) statement 15 PubMed, EMBASE, and MedRxiv databases were applied for searching studies published from December 2019 to April 2020 in China. To identify all the articles displaying the renal injury and impairment in COVID -19, we used the following keywords or search terms alone and in combination: "novel coronavirus", "China", "HCoV", "nCoV" "Wuhan", "COVID-19" . CC-BY-NC-ND 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 June 3, 2020. . https://doi.org/10.1101/2020.05.28.20116400 doi: medRxiv preprint "SARS-CoV-2", "clinical", "laboratory", "kidney", "Acute Kidney Injury", "proteinuria" and "hematuria". Detailed search strategies were illustrated in Figure 1 . Inclusion criteria are as follows:(1) comparative studies: randomized controlled trials RCTs or non-RCTs published only restricted in English; (2) patients in the studies should be confirmed to have been infected by (3)studies containing information about the clinical or laboratory characteristics (4) studies containing the comorbidities of kidney dysfunction and the outcome of kidney impairment. Exclusion criteria are (1) studies that less than 10 patients were included; (2) case reports, editorials, comments, non-clinical studies, reviews, studies without reliable information; (3) studies with special populations (e.g., only focused on children or severe or death cases). Prevalence of comorbidities and clinical manifestations of kidney damage, including AKI, proteinuria and hematuria, together with laboratory indexes of kidney impairment (confirmed by elevation of Scr, BUN and D-dimer) were extracted from the identified studies. The subgroup measure parameters were to compare the incidences of AKI and the mean differences of the three laboratory indicators among ICU and Non-ICU cases (severe and non-severe data as the second choice if ICU data was not provided). Cochrane Collaboration's tool was applied to evaluate the risk of bias. All analyses were performed using OpenMeta Analyst (version 12.11.14) (http://www.cebm.brown.edu/openmeta/) and Review Manager (version 5.3). Forest plots were used to depict the incidences of clinical and laboratory features of kidney dysfunction of . CC-BY-NC-ND 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 June 3, 2020. . https://doi.org/10.1101/2020.05.28.20116400 doi: medRxiv preprint COVID-19 patients. The odds ratio (OR, 95% confidence intervals (CI)) and mean differences (MD, 95% confidence intervals (CI)) were used to illustrate the comprehensive effects of COVID-19 occurring in ICU/severe patients and non-ICU/non-severe patients. And I 2 statistics were used to assess the statistical heterogeneity. The fixed-effect model was used if I 2 < 50% and the random effect model was used if I 2 ≥ 50% 8 . The funnel plots were used to show the risk of publication bias. At initially, we have searched a total of 838 studies after 231 duplicate studies were identified. Table 1 . And we also described the prevalence of the complications of kidney injury on clinic and laboratory features. The majority of studies were performed in Wuhan and . CC-BY-NC-ND 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 June 3, 2020. . https://doi.org/10.1101/2020.05.28.20116400 doi: medRxiv preprint other cities in China. Among all selected studies, the infected men accounted for a more substantial proportion than women and the men to women ratio was 1.2. The mean age of the participants was 52.5 years (95% CI, 49.7-55.4). Our outcome of meta-analysis for identified studies suggested that the AKI occurred 7.7% (95% CI 4.5-10.9%) in COVID-19 patients (Figure 2A) . According to the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines 16 To identify the risk factors for critical illnesses of COVID-19 patients, we then analyzed the relevance of the AKI and the three laboratory indexes with the clinical severity through comparing the incidences of AKI and mean differences of those biomarkers between ICU/severe and non-ICU/non-severe cases. Following the results of the heterogeneity test were all shown as I 2 <50%, we applied the fixed-effect model for further investigations. For AKI, the result from 6 studies including 1813 patients showed that the AKI occurred statistically . CC-BY-NC-ND 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 June 3, 2020. . (Figure 2A-D) . AKI is a risk factor of proteinuria and subsequently can be developed into chronic kidney disease(CKD) 18 . Here, we sought to further explore the clinical effects of kidney impairment caused by COVID-19, and we analyzed another two clinical features among COVID-19 patients. The results show that the most prevalent of kidney injury comorbidities were proteinuria (42.0%, 95%CI 30.4%-53.7%) ( Figure 3A) and hematuria (30.3%, 95%CI 20.6%-40.1%) (Figure 3B ) with high heterogeneity (both I 2 > 80%). In the end, the funnel plots displayed symmetrical distributions of the effect sizes of AKI, Scr, BUN and D-dimer, and presented no obvious publication bias (Figure 4A-D) . The COVID-19 has affected hundreds of millions of people posing a huge healthy threaten and bring a major burden to public healthcare institutions around the world. Compared with the other two pathogenic coronaviruses family members SARS-CoV and MERS-CoV, SARS-. CC-BY-NC-ND 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 June 3, 2020. . https://doi.org/10.1101/2020.05.28.20116400 doi: medRxiv preprint CoV-2 is higher contagious causing global pandemic, whereas each of which has its own clinical manifestation. Studies have been reported that SARS-CoV-2 is sharing highly 79.6% genome sequence identity as well as high molecular structure similarity with SARS-CoV 4,19 . Therefore, SARS-CoV-2 uses ACE2 as a cellular entry receptor as SARS-CoV 4,20 . ACE2 is highly expressed in multiple systems and tissues, mainly in the respiratory, cardiovascular, renal and gastrointestinal systems 7 . In addition to respiratory diseases and cardiac damage caused by SARS-CoV-2 through ACE2, we still need to consider the possibility of kidney effects on COVID-19 patients. The meta-analysis was based on data from 19 studies with confirmed COVID-19 cases in China. In all cases, men were a more significant population around 55% than women, which has similar infection characteristics as MERS and SARS 21, 22 . Also, aged and people with other comorbidities, especially cardiovascular diseases, are more likely susceptible to COVID-19 23 . Our meta-analysis has shown that the prevalence of AKI is approximately 7.7%, and other laboratory biomarkers reflecting renal injuries such as increased Scr, BUN and D-dimer were presented in 6.6%, 6.2%, 49.8%, respectively. Moreover, the clinical features of kidney dysfunction are even higher than cardiovascular diseases in COVID-19 patients, proteinuria is 42% and hematuria is 30.3%, while hypertension and diabetes were showed around 8% and 5% in Jing Yang's study 9 . When compared the ICU/severe and non-ICU/non-severe cases, our results have demonstrated that the AKI happened 17-folds higher in critical condition, while the incidence of acute cardiac injury was around 13-folds higher in severe disease in Bo Li's study 8 . At all, the kidney injury is more susceptibility than cardiac damage so that we should pay more attention to protecting the normal function and recovery of kidney . CC-BY-NC-ND 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 June 3, 2020. . https://doi.org/10.1101/2020.05.28.20116400 doi: medRxiv preprint Due to the restriction of clinic information and most of the studies did not include in the death cases and the mortality of COVID-19, the association between kidney impairment and COVID-19-induced death was not be analyzed in our meta-analysis. We still need to follow-up those COVID-19 patients in the future, as the most relevant clinical predictors are chronic kidney disease for the death in SARS patients. Therefore, the chronic diseases community will play a critical role in the management and treatment of patients affected by this epidemic disease. However, there are still some limitations for this meta-analysis. Firstly, due to the information missing from the literature, we hardly could include study compared the complications of kidney injury between ICU/severe and non-ICU/non-severe patients. In which cases, we did not perform sensitivity analysis and subgroup analysis for proteinuria, hematuria or uric acid. Secondly, we found that the high statistic heterogeneity in the prevalence of kidney injury analysis. The reasons are related to the study designs and significant variations among studies in the sample sizes. Thirdly, therapies under investigation for COVID-19 may have kidney side effects as lots of drugs are nephrotoxic such as aminoglycosides, ACE inhibitors and nonsteroidal anti-inflammatory drugs(NSAIDs), we are not sure whether some clinical data we got have such possibility involved, and we could not rule out the influences caused by drugs on kidney during the hospitalization. There are some explanations for kidney injury during the COVID-19 infection episodes. Firstly, ACE-2 distributes on tubular epithelial cells of the kidney with a higher expression level compared to the lung. Thus, the kidney is also a direct aim organ attacked by SARS-CoV-2 entering into target cells through ACE-2 acting as the way in the lung. Secondly, the crosstalk relationship between lung and kidney. Kidney damage can be caused by circulating . CC-BY-NC-ND 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 June 3, 2020. . https://doi.org/10.1101/2020.05.28.20116400 doi: medRxiv preprint inflammatory factors such as tumor necrosis factor (TNF)-α and interleukin (IL)-6, which are originated from pneumonia, happened in the lung. Furthermore, the local inflammatory response from injury and death renal cells will accelerate damage in the development of AKI as well as other organs 24, 25 . On the other hand, we still need to analyze the reasons accounting for underestimating kidney impairment in COVID-19 patients in clinic. Firstly, the laboratory tests of blood chemistry analysis, including Scr and BUN, will only elevate into abnormal range when kidney lost at least 50% function because of the potent compensatory ability of kidney. From our results, we also found that the proportions of aberrant urinalysis were more than the percentage of increased plasma biomarkers. Secondly, the difficulty of precise diagnosis of AKI is another possible aspect responsible for the underrating of AKI. The detection rate of AKI mainly depends on the fluctuation of Scr and the frequency of Scr testing. And a higher incidence of AKI will be detected with adjusted denser Scr testing frequency. Therefore, more accurate strategies should be applied to the clinic when considered AKI 26 . In conclusion, SARS-CoV-2 causes renal injury progressing to severe AKI. At the same time, AKI is a life-threatening complication associating with a severer condition in COVID-19 patients. Therefore, we should focus more attention to kidney damage at the early stage when patients are confirmed been infected by COVID-19. There are several biomarkers can be used for monitoring the kidney function such as the level fluctuation of creatinine and urine output with the volume and hemodynamic status, and some novel indicators also should be added in for precisely stratifying the AKI severity like TIMP-2 (tissue inhibitor of metalloproteinase 2 . CC-BY-NC-ND 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 June 3, 2020. . https://doi.org/10.1101/2020.05.28.20116400 doi: medRxiv preprint (TIMP-2) and insulin-like growth factor binding protein 7(IGFBP7) 27 . Moreover, to reduce the possibility of developing into critically illness and the mortality risk for COVID-19 patients, applying more protective measures and supportive medication interventions is necessary, which has a significant influence for the kidney care of patients, including but not limited to renal replacement therapies like blood filtering and purification treatments, the application of drugs with mild kidney adverse effects etc. None. Central South University 31801-160170002. 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 June 3, 2020. . . CC-BY-NC-ND 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 June 3, 2020. . https://doi.org/10.1101/2020.05.28.20116400 doi: medRxiv preprint AKI, acute kidney injury; Scr serum creatinine; BUN blood urea nitrogen. 2/19/2020 265 Shanghai NA NA ------ . CC-BY-NC-ND 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 June 3, 2020. . https://doi.org/10.1101/2020.05.28.20116400 doi: medRxiv preprint Figure 2 A Acute kidney injury . CC-BY-NC-ND 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 June 3, 2020. . https://doi.org/10.1101/2020.05.28.20116400 doi: medRxiv preprint B Serum creatinine C Blood urea nitrogen . CC-BY-NC-ND 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 June 3, 2020. . https://doi.org/10.1101/2020.05.28.20116400 doi: medRxiv preprint D D-dimer . CC-BY-NC-ND 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 June 3, 2020. . https://doi.org/10.1101/2020.05.28.20116400 doi: medRxiv preprint 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 June 3, 2020. . https://doi.org/10.1101/2020.05.28.20116400 doi: medRxiv preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 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