Dear Editor,
Of no doubt, the whole world is passing through a potentially life-threatening and
economically destructive global pandemic caused by the novel coronavirus (COVID-19;
SARS-CoV-2; previously known as 2019-nCoV) [1]. The clinical course of infection is
widely unpredicted and variable, ranging from asymptomatic infection to multi-organ
system failure and death [2–4]. Nevertheless, the survival rate among patients with
COVID-19 and superimposed acute kidney injury (AKI) remains unclear [5,6]. Hence;
we ushered a systemic review and meta-analysis exploring the survival outcome of COVID-19
subjects who developed severe AKI, the latter defined as subjects who require acute
renal replacement therapy (RRT) or meet the Kidney Disease Improving Global Outcome
(KDIGO) definition of AKI stage III. We included all studies performed on human beings
for which baseline creatinine, occurrence of AKI stage III and/or need for acute RRT
were reported and excluded case reports, review articles, or studies assessing clinical
characteristics and conference abstracts. Ethical approval was not required for this
work due to use of anonymous data that is publicly available. A systematic review
in Pubmed, Medline, Embase and Cochrane databases to select studies that met the inclusion
criteria was performed by 3 authors (H.A, M.M, A.A). The search terms used were (coronavirus,
COVID-19, SARS-COV-2 and (mortality, survival, outcomes, dialysis, acute renal failure,
acute kidney injury, renal replacement therapy). These search terms were individually
used and then combined in different databases. References within the chosen studies
were reviewed. All the included studies were reviewed by supervising authors. Any
disagreement among authors collecting the data was investigated by supervising authors.
Consensus among all authors was essential to include the studies in the systematic
review. The following data were collected: name of the first author, journal title,
publication date, place of the study, sample size, baseline creatinine, relative risk
and confidence intervals for association of acute renal failure and mortality. We
followed the recommendations of Cochrane collaboration and the Quality of Reporting
of Meta-analyses guidelines [7,8]. STATA package-15 was used for statistical analysis.
We combined all study-specific estimates using inverse-variant weighted averages of
logarithmic relative risk in random effects model (REM). Confidence interval including
the value of one was used evident for statistically significant estimate. Heterogeneity
was evaluated using Higgins I-squared statistic. Heterogeneity was estimated when
the level of p value was <.1. Results of the REM were spread out on the forest plot
graph. The Newcastle-Ottawa score was used to evaluate the quality of the papers included.
Egger's test was used to assess publication bias. A total of 2290 abstracts were reviewed.
Out of six studies included in the systematic review, only three studies met the inclusion
criteria and were pooled into a meta-analysis (PRISMA diagram, Figure 1). Due to lack
of a controlled survival group (only severe AKI subjects were included), the studies
by Zhang et al. and Shi et al. were not included in the meta-analysis [9,10]. As compared
to Ruan et al., Cheng et al.’s study was more recent, included a larger sample size
and since both shared the same cohort, only the latter was included in our meta-analysis
[5,11]. The baseline characteristics of the studies included are shown in Table 1.
The Newcastle-Ottawa score of the included studies is shown in Table 2. REM showed
that severe AKI is associated with higher risk of mortality (relative risk = 3.08,
confidence interval ranges from 1.54 to 6.19) as shown in Figure 2. There was evidence
of heterogeneity with I-squared =90% and p < .001. Publication bias was shown in the
funnel plot analysis in Figure 3. By applying Egger's test for assessment of bias,
there was evidence of small studies effect with p = .93.
Figure 1.
PRISMA diagram for the systematic review.
Figure 2.
Forest plot analysis.
Figure 3.
Funnel plot.
Figure 4.
Random effects model after excluding Yang et al.
Table 1.
Baseline characteristics of studies included in the systematic review.
Name
Journal
Date of Publication
Name of hospital
Study population
Baseline creatinine Mean (standard deviation)
Yang et al.
Lancet Respiratory Medicine
March 2020
Intensive care unit (ICU) of Wuhan Jin Yin-tan hospital (Wuhan, China)
52 patients
76・3 (27・4) umol/L in survivors80・7 (32・3) umol/L in non-survivors
Cheng et al.
Kidney International
March 2020
Tongji Hospital, Wuhan, China
701 patients
77 ( 31) umol/L
Zhou et al.
Lancet
March 2020
Jinyintan Hospital and Wuhan Pulmonary Hospital-China
191 patients
8 patients had baseline creatinine >133umol/L
Zhang et al.
medRxiv
March 2020
Eastern Campus, Renmin Hospital, Wuhan University, China
82 patients
78 umol/L
Ruan et al.
Intensive care medicine
March 2020
Jin Yin-tan Hospital and Tongji Hospital,
150 patients
91 in non-survivors 72 in survivors
Shi et al.
medRxiv
March 2020
Department of General Surgery, Renmin Hospital of Wuhan University,
101 patients
139.8 ± 22.83 umol/L
Table 2.
Newcastle-Ottawa score of the included studies.
Study ID
Exposed cohort representative
Non exposed cohort selected from same source
Exposure ascertained
Outcome of study was not present at start of the study
Comparability
Adequate assessment
Follow up was long nough
Adequate follow-up
Quality score
Yang et al.
yes
Yes
yes
yes
1
yes
yes
yes
8
Cheng et al.
yes
Yes
yes
yes
1
yes
yes
yes
8
Zhou et al.
yes
Yes
yes
yes
1
yes
yes
yes
8
Zhang et al.
yes
No
yes
yes
0
yes
yes
yes
5
Ruan et al.
Yes
Yes
Yes
Yes
1
Yes
Yes
yes
8
Shi et al.
yes
No
yes
yes
0
yes
yes
no
5
To decrease risk of heterogeneity, REM was repeated after excluding Yang et al (Figure
4). The association of severe AKI with mortality persisted (relative risk = 4.19,
95% CI 3.31 - 5.31). There was no evidence of heterogeneity with I-squared = 0%, p = .68.
There was no evidence of publication bias when applying Eggers test (p < .05) or funnel
plot analysis (Figure 5). Our meta-analysis supports that mortality is significantly
higher in patients with severe AKI in patients with COVID-19. To date, the published
incidence of AKI among patients with COVID-19 is highly variable. It has been reported
to occur in up to 27% of patients with COVID-19 [12]. Our meta-analysis included three
studies addressing mortality in COVID-19 patients with superimposed AKI. Cheng et al.,
included 701 COVID-19 confirmed cases. AKI stage III occurred among 14/701 (2%) of
the patients and was associated with an increased risk of in-hospital mortality (hazard
ratio = 9.81, 95% CI:5.46-17.65) [5]. Similarly, Yang et al. included 52 COVID-19
confirmed cases in their study and found that 8 out of 9 subjects who required RRT
did not survive [13]. Mirroring Yang et al.’s results, Zhou et al., in a study that
included 191 COVID-19-CC, 10 out of 10 subjects who required RRT did not survive [14].
In addition, the investigators reported that out of 33 confirmed COVID-19 cases who
developed AKI, 32 patients did not survive [14]. The high mortality in COVID-19 patients
and severe AKI, even with RRT, could be due to the kidney-lung crosstalk during COVID-19
infection and amplification of inflammation during AKI in a cohort with high incidence
of acute respiratory distress syndrome [15]. Based on the available limited published
data, severe AKI in patients with COVID-19 is an ominous clinical predictor and is
associated with high mortality. Further studies are needed to understand the factors
associated with worse outcomes among COVID-19 patients with AKI. Understanding those
factors may guide care providers in making more informed dialysis eligibility decisions
under conditions where resources are extremely limited.
Figure 5.
Funnel plot analysis after excluding Yang et al.