Started in December 2019, after setting in Wuhan, China, the SARS-CoV-2 infection, responsible to the illness officially nominated as coronavirus disease 2019 (COVID-19), quickly spread to other regions, affecting several countries worldwide and, at the end of the 2020, on 27 December, the global number of infected and killed individuals by COVID-19 have been over 79.2 and 1.7 million, respectively.1 Frequent manifestations of COVID-19 include characteristic symptoms of an acute respiratory illness, as fatigue and dry cough, but may also occur others signs and symptoms as dyspnea, whereas acute respiratory distress syndrome (ARDS) is the main pulmonary complication.2 As well as the lung, other organs can also be affected, such as the kidney and heart.2–6

Cheng et al.3 analyzed the occurrence of renal abnormalities in patients with COVID-19 from a Wuhan hospital and observed higher rate proteinuria, elevated serum creatinine and elevated blood urea nitrogen (BUN). The authors reported that the acute kidney injury (AKI) incidence was 5.1% and this complication was significantly associated with worse prognosis. In other large study, involving 5499 patients with COVID-19 from 13 hospitals in the New York metropolitan area,4 the AKI incidence was 36.6% and, just like in the Chinese study, the AKI occurrence in the North American patients also was associated with worse outcomes. In addition, the risk factors associated with AKI in this study were advanced age, comorbidities, need for ventilation and drug-associated.

Several studies report the occurrence of AKI and others adverse kidney events in hospitalized patients with COVID-19.2–10 However, the involvement of kidney and the epidemiological burden of AKI in patients with COVID-19 is still unclear and needs to be better studied.2–5 Therefore, this study aimed to determine the AKI incidence in patients hospitalized with COVID-19. The results of this systematic review will help healthcare teams to carry out a care plan with greater attention to the kidney function of patients with COVID-19.

This systematic review was conducted from a comprehensive search in the main biomedical databases of the world and included 30 studies published until the third week of Jun 2020, which together report data from more than 18,000 patients (table 1). By the meta-analysis from 28 studies, it was verified that 9.2% (CI 4.6–13.9%) of adult patients hospitalized with COVID-19 presented AKI (Fig. 2). Among patients that required admission to ICU the AKI incidence was substantially higher (32.6%, CI 8.5–56.6%) (Fig. 3).

We verified that the meta-analysis of AKI overall and ICU incidence presented high heterogeneity and, possible causes for this may be related to recognized differences among the studies, especially, with regard to design, number of included participants and follow-up time. The number of enrolled patients varied between 16 patients in a single-center retrospective study conducted in the USA33 and 5700 enrolled in a retrospective multi-center study also conducted in the USA.7

In the research of Hirsch et al.,4 53.2% of patients with AKI were in the ICU. Yu et al.10 assessed 226 critically patients with COVID-19 in 19 ICUs from Wuhan, China, and the AKI incidence was 25.2%. In one study carried out in South Korea, AKI incidence in the ICU was 61.5%.16

From what is known so far, among the mechanisms involved in the AKI occurrence in patients with COVID-19 is the triggering of the cytokine release syndrome (CRS), also known as “cytokine storm”, with consequent endothelial damage, mitochondrial dysfunction, hypovolemia, and hypercoagulability.37,38 Moreover, the direct viral damage, mediated by co-expression and activity of angiotensin-converting enzyme 2 (ACE2) and cellular transmembrane serine proteases (TMPRSSs), can cause kidney damage cells and apoptosis, especially, in podocytes and proximal straight tubule cells.39,40

These multiple pathophysiological depletions can be observed in the clinical practice by identifying some renal abnormalities.3,7,21,32,37 By data analysis of 333 patients, Pei et al.32 observed that 75.4% presented renal abnormalities, being proteinuria and hematuria the most frequent. These are also the most frequent abnormalities observed in the research of Cheng et al.3 Furthermore, data from other studies in which the AKI occurrence were reported also showed that the patients had elevated levels of serum creatinine and BUN.4,8,16,17,21,26,27,30,31

We performed subgroup analyses to minimize the high heterogeneity observed in the global analysis (with all studies included) Even so, the high heterogeneity remained in the subgroup analysis. Even grouping the studies in which the patients had similar characteristics, the difference in the number of patients enrolled, possibly, was the main cause of maintaining high heterogeneity.

According to geographic location of these COVID-19 cases, the AKI estimate incidence was vastly higher at USA (22.9% [CI −2.0–47.8%]) than China (3.9 [CI 1.7–6.2%]) (S3 File). This expressive difference in the AKI incidence between the two countries, could be explained at least in part, by the fact that Occidental populations have a more pronounced expression of the receptor ACE2 in podocytes and proximal straight tubule cells.39 Hirsch et al.4 identified higher AKI incidence among black (20.8%) and white (41%) patients than in Asians (8.1%). However, other epidemiological and experimental studies, including data with patients from different races are needed to confirm this preliminary evidence.

In this systematic review, high AKI incidence was also found among elderly (S4 File) and patients with early hospitalization (S5 File). Hirsch et al.4 identified that advanced age is an independent risk factor for AKI, and the highest incidence of this complication on COVID-19 patients was verified in the first days of hospitalization. Yang et al.21 highlighted that elderly patients had a worse prognosis after COVID-19 infection and 14% of patients with hospitalization≤7 days had essential organ injury, including AKI.

Thereby, AKI incidence seems to be linked to the shorter onset time of COVID-19, given by time between symptoms onset and hospitalization. Pan et al.39 report that co-expression of the ACE2 and TMPRSS genes in kidney cells were similar to that seen in the lung and other organs. In addition, the authors highlight that the time between detection of COVID-19 in blood and AKI occurrence was around one week.

Based on the findings of this study and in the literature, it is reasonable to believe that the AKI occurrence in adult patients hospitalized with COVID-19 is as early as acute respiratory failure, and the health team must be attentive to the predictive signs of AKI occurrence, as described in KDIGO (Kidney Disease: Improving Global Outcomes) guidelines for care guidance aiming the early diagnosis and treatment.3,32,37

AKI incidence among patients with ARDS (4.3% [CI 1.8–6.8%]) was lower than in those with ACI (9.3% [CI 1.8–16.9%] (S6 File). By the correlations test, ARDS and ACI showed a direct and statistically significant correlation of greater strength with the AKI incidence (S8 File). Shi et al.6 verified that ACI, with an incidence of 19.7%, was significantly associated with AKI (8.5%) and ARDS (58.5%) incidences. In a study performed by Guo et al.36 with patients from Wuhan, China, the authors observed that myocardial injury was significantly associated with worse outcome. In addition, the AKI and ARDS incidences were higher in patients with elevated troponin T levels, compared to those with normal levels.

In a robust study from the USA, the need for mechanical ventilation (one of the ARDS consequences), as well as cardiovascular disease (including heart failure) were significant risk factors for AKI occurrence.4 In the COVID-19 infection, injury in the lung-kidney-heart triad is associated with direct viral damage due to high local expression of ACE2 receptor, resulting in organ crosstalk (as alveolar damage, renal compartment syndrome, cardiomyopathy, cardiorenal syndrome and tubular toxicity) and systemic effects.

AKI estimate incidence in patients with secondary infection was 31.6% (CI 12.3–51.0%) and among those sepsis/shock was 4.7% (CI 2.1–7.4%) (S7 File). In the correlation tests, the incidence of these complications was also directly proportional to the AKI incidence (S9 File). Among selected studies, the rates of secondary infection and sepsis/shock were between 2.8%30 and 75%33 and between 0.3%9 and 65%,34 respectively. These complications result in hemodynamic instability, contributing to the increased need for RRT and the mortality rate among patients.37–40

We emphasize that the studies included in this review present data collected at the beginning of the pandemic, when there were still many uncertainties about the pathophysiological mechanisms involved in the occurrence of AKI in patients with COVID-19. Thus, the possible difficulty in identifying the occurrence of AKI in critically ill patients with sepsis/shock before they died may, at least in part, justify the low incidence of AKI in patients with COVID-19 and sepsis/shock, compared to those with secondary infection. Therefore, we encourage the conduction of other review studies like this one, to identify possible changes in the current epidemiological profile of AKI in patients with COVID-19 compared to what we present in this review, which brings data from studies conducted at the beginning of the pandemic.

The estimated proportion of RRT need was 3.2% (CI 1.1–5.4%) and the estimated incidence of mortality was 50.4% (CI 17.0–83.9%) (S12). Continuous RRT (CRRT) was the predominant dialysis technique reported by studies. Hu et al.31 reports that 22.3% of patients studied required CRRT and, among those that required ICU admission the CRRT rate was 26.7%. The rate of death in AKI was between 35.7%21 and 100%,19,35 and the mortality rate was higher among patients who required CRRT.26,34

This systematic review and meta-analysis have some limitations. First, the most selected studies were from China and with considerable risk of methodological biases once they come from retrospective case series or observational analysis. In addition, most studies report data from a restricted sample of patients. The funnel plots (S11 and S12 Files) suggest a possible publication bias and bias related, especially to the fact that most studies were not designed to assess AKI incidence and, as consequences, the definition of AKI was unclear in most of these studies. Although KDIGO was reported as being used in several studies, information regarding rate and definition of baseline serum creatinine, urine output criteria or period of observation to define AKI were not described. In the analyses of the studies included in this systematic review we focused our efforts on identifying the incidence of AKI and, because of that, we did not collect data on risk factors for AKI occurrence. Thus, we recommend that future studies include such an analysis to better understand the epidemiology of AKI in COVID-19.

The occurrence of AKI is frequent among adult patients hospitalized with COVID-19, and affects on average, up to 13.9% of these patients. It is believed that AKI occurs early and in parallel with lung injury. The elderly population, with acute cardiac injury and secondary infection, is among the group at highest risk for AKI.

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

The authors declare that there is no conflict of interest.