key: cord-0849357-k5gh0s6y
authors: Ouyang, Lichen; Gong, Yeli; Zhu, Yan; Gong, Jie
title: Association of acute kidney injury with the severity and mortality of SARS-CoV-2 infection: A meta-analysis
date: 2020-09-02
journal: Am J Emerg Med
DOI: 10.1016/j.ajem.2020.08.089
sha: d40ac1b878b219cb61db1788c638ec368d452932
doc_id: 849357
cord_uid: k5gh0s6y

BACKGROUND: we aimed to explore the relationship of acute kidney injury (AKI) with the severity and mortality of coronavirus disease 2019 (COVID-19). METHODS: A systematic literature search was conducted in PubMed, EMBASE, Scopus, Web of Science, MedRxiv Database. We compared the laboratory indicators of renal impairment and incidences of AKI in the severe versus non-severe cases, and survival versus non-survival cases, respectively. RESULTS: In 41 studies with 10,335 COVID-19 patients, the serum creatinine (sCr) in severe cases was much higher than that in non-severe cases (SMD = 0.34, 95% CI: 0.29–0.39), with a similar trend for blood urea nitrogen (BUN) (SMD = 0.66, 95%CI: 0.51–0.81), hematuria (OR = 1.59, 95% CI: 1.15–2.19), and proteinuria (OR = 2.92, 95% CI: 1.58–5.38). The estimated glomerular filtration rate decreased significantly in severe cases compared with non-severe cases (SMD = -0.45, 95% CI: −0.67–0.23). Moreover, the pooled OR of continuous renal replacement therapy (CRRT) and AKI prevalence for severe vs. non-severe cases was 12.99 (95%CI: 4.03–41.89) and 13.16 (95%CI: 10.16–17.05), respectively. Additionally, 11 studies with 3759 COVID-19 patients were included for analysis of disease mortality. The results showed the levels of sCr and BUN in non-survival cases remarkably elevated compared with survival patients, respectively (SMD = 0.97, SMD = 1.49). The pooled OR of CRRT and AKI prevalence for non-survival vs. survival cases was 31.51 (95%CI: 6.55–151.59) and 77.48 (95%CI: 24.52–244.85), respectively. CONCLUSIONS: AKI is closely related with severity and mortality of COVID-19, which gives awareness for doctors to pay more attention for risk screening, early identification and timely treatment of AKI.

Coronavirus disease 2019 (COVID- 19) , a newly emerging acute respiratory disease, is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and causes substantial morbidity and mortality [1] . As of 12 June 2020, 7519566 COVID-19 cases have been confirmed and 419447 people died from COVID-19 in more than 200 countries around the world. Most patients with COVID-19 are considered as non-severe patients and recover from this infection. However, the symptoms in about 10% of COVID-19 patients are severe and progress rapidly to critical conditions, including organ dysfunctions, such as acute respiratory distress syndrome (ARDS), acute cardiac injury, acute kidney injury (AKI) and even death [2] . meta-analysis to investigate the association of AKI with the severity and mortality of SARS-CoV-2 infection.

The systematic review and meta-analysis were performed according to the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions and reported based on Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines [6, 7] . This meta-analysis has no protocol.

Articles published from December 2019 to 8 June 2020 in Pubmed, EMBASE, Web of Science, Scopes, and MedRxiv Database were searched. To identify all the articles displaying the renal impairment in COVID-19, we used the following terms alone or in combination for literature search: "SARS-CoV-2", "COVID-19", "2019-nCoV", "nCoV", "COVID19", "coronavirus", "severe acute respiratory rate ≥30 bpm; II, finger SpO 2 ≤93% at rest; III, ARDS or arterial partial pressure of oxygen/fraction of inspired oxygen≤300 mmHg; IV, respiratory failure (requiring mechanical ventilation); V, shock; VI, other organ failure (requiring ICU monitoring and treatment) [9] .

Two investigators worked independently to decide which studies should be included, and the disagreement was resolved by a third investigator. Data was extracted from selected studies including the first author's name, publication data, sex, average age, numbers of patients and study type. In addition, laboratory examinations of renal impairments including BUN, sCr, eGFR, proteinuria and hematuria, and incidence of AKI and CRRT were also extracted. The data shown as median and interquartile range was transformed into mean and standard deviation (SD) according to the formula below (http://www.math. hkbu.edu.hk/~tongt/papers/median2mean. html). The prevalence of proteinuria, hematuria, CRRT and AKI as well as average means of BUN, sCr and eGFR were evaluated between severe and non-severe group or survival and non-survival group, respectively.

All data was analyzed by the Review Manager meta-analysis software (version 5.4).

The standardized mean differences (SMDs) and 95% confidence intervals (CIs) were calculated for continuous data. The odds ratios (ORs) and 95% CIs were calculated for dichotomous data. The magnitude of heterogeneity between different studies was tested using I 2 statistics. If there was no evidence of between studies heterogeneity (I 2 ≤ 50%), a fixed-effects model was used to calculate. Otherwise, a random-effects model was selected [10] . The Z score was tested for overall effect, with significance considered as P<0.05. Publication bias was evaluated by funnel plot if the number of included studies > 10.

We searched a total of 2893 articles according to the search terms. Firstly, duplicated articles (n=597) were excluded. After reviewing the titles and abstracts, case reports, reviews, letters, meta-analysis, editorials, guidelines, comments, not relevant studies and sample size less than 20 (n=2150) were ruled out. 94 articles were excluded after thoroughly reviewing the full texts due to the following reasons: studies focused on special populations (n=35); studies without available data (n=47), studies with sample less than 20 (n=12). Finally, 52 articles[1-4, 9, with 14094 patients were included in our meta-analysis. Figure 

As shown in Table 1 , most of studies were from China, and six studies were published from other countries [11,12,25, 15, 19, 22, 24, 25, 35, 40, 48, 52, 53] . The incidence of AKI and CRRT during SARS-CoV-2 infections was evaluated between the severe versus non-severe cases or survival versus non-survival cases, respectively.

As shown in figure 2A , sCr was measured in nine studies among 2345 patients. The heterogeneity test of sCr was shown as I 2 =53%, thus we applied the random-effects model for further investigation. The following results elucidated that sCr was significantly higher in non-survival group than that in survival group [SMD=0.97, group ( Figure 2C ). The heterogeneity test of AKI was shown as I 2 =0. Pooled analysis of four studies among 792 COVID-19 patients revealed that the incidence of AKI was statistically higher in non-survival group (30.72%) compared with survival group 

As illustrated in figure 3 As severity of illness was related with complication in COVID-19, we also evaluated the incidence of AKI in severe and non-severe group ( Figure 5A ). The heterogeneity test of AKI was shown as I 2 =20%. 19 studies among 4968 COVID-19 patients reported that the incidence of AKI was shown to be 26.74% in severe group, which was significant higher than that in non-severe group In addition, we also performed meta-analysis on the incidence of hematuria of 664 COVID-19 patients with no statistical heterogeneity among 4 studies (I 2 =47%). The incidence of hematuria in severe group was statistically higher compared with non-severe group [OR=1.59, 95% CI (1. 15-2.19) , Z=2.83, P=0.005] ( Figure 5C ).

Our meta-analysis including 14094 subjects from 52 studies explored the potential relationship between renal impairment as well as AKI and the clinical outcome J o u r n a l P r e -p r o o f Journal Pre-proof (severity and mortality) of COVID-19 patients. To our knowledge, this is the first systemic review and meta-analysis which evaluated the kidney function and prevalence of AKI between survival and non-survival cases. We found that the prevalence of AKI in non-survival cases was 30.72%, which was approximately 77.48-fold higher than that in survival cases. Furthermore, patients who died of COVID-19 displayed higher baseline of sCr and BUN as well as higher application rate of CRRT than the survival cases. Meanwhile, our results including severe and non-severe cases (41 studies, 10335 patients) demonstrated that the overall rate of AKI in severe cases was 13.16-fold higher compared with non-severe cases. The levels of sCr and BUN were shown elevated, while eGFR was decreased in severe cases compared with non-severe cases. In addition, the average ratio of proteinuria, hematuria and CRRT were 2.92-fold, 1.59-fold and 12.99-fold in severe cases compared with those in non-severe cases, respectively.

Currently, the exact mechanism of renal impairment involved in COVID-19 remains unclear. One potential explanation is direct virus attack mediated via angiotensin-converting enzyme 2 (ACE2). RNA sequencing studies found that ACE2, the novel protein of coronavirus receptor, was highly expressed in proximal renal tubules, which could explain that the urinary analysis was obviously abnormal in COVID-19 patients [58] . Hence, early detection of urinary analysis is important for preventing the occurrence of AKI. In addition, hyper-activated immune response may be partly responsible for the development of kidney damage. Clinical studies have shown that the levels of inflammatory cytokines in severe patients are significantly J o u r n a l P r e -p r o o f Journal Pre-proof increased compared with mild patients [30] . A recent biopsy pathology result of a COVID-19 patient with ARDS demonstrated that the numbers of CD4 + and CD8 + T cells in peripheral blood were greatly reduced, while T cells were excessively activated [59] . These above findings indicated that pathological waterfall-like cytokines storm caused by immune dysregulation may be involved in the occurrence and development of AKI and multiple organ dysfunctions. Additionally, patients with COVID-19, especially severe and critical cases, are prone to complications such as sepsis, shock, and hypovolemia, which could cause the occurrence or aggravation of AKI through excessive inflammatory responses, apoptosis, and mitochondrial stress [60] . Therefore, optimizing fluid volume and maintaining hemodynamic stability are crucial for severe COVID patients to ensure adequate and effective perfusion pressure of the kidney, which could prevent the occurrence or progression of AKI.

There are strengths of this meta-analysis. To the best of our knowledge, this is the first large meta-analysis which performed a pairwise comparison of kidney function indicators and prevalence of AKI in severe vs. non-severe or non-survival vs. survival cases, respectively. Secondly, we have included a large number of studies covering six countries, with patient population above fourteen thousand. Finally, our meta-analysis 

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