The occurrence of AKI in critically ill COVID-19 patients is high. In this study, we observed an incidence of 56% in COVID-19 patients undergoing IMV, 36% corresponding to severe AKI, and 8.3% of patients requiring RRT. As previously reported, AKI was associated with higher mortality. The factors associated with AKI development were increasing age and body mass index, laboratory parameters at the initiation of IMV, and vasopressor use. Interestingly, treatment with a standardized DXM regimen reduced the incidence, severity, and mortality of severe AKI after adjusting for other factors. This is one of the first large cohorts of COVID-19 patients on IMV to show this significant reduction in AKI episodes and their severity with the use of DXM.
Several studies from multiple centers have reported an elevated incidence of AKI in COVID-19 patients admitted to the ICU, ranging from 30 to 75% for AKI of any stage, 21 to 56% for severe AKI (stages 2 or 3), and 6 to 39% for AKI requiring RRT [17–22]. In this study, AKI incidence was well between these ranges: 56% AKI of any stage, 36% severe AKI, and 8% for AKI requiring RRT. The high variability in these numbers is explained by the well-reported variation between hospitals [21], the different criteria for ICU admission, the timing of the study relative to the pandemic waves [5, 17], and characteristics of the population admitted to the ICU, among other factors.
An important factor that has been associated with AKI development is the use of IMV [20, 23, 24]. For example, in previous reports from critically ill COVID-19 patients were all patients received IMV [5, 19], the incidence of AKI was 52 to 75%, and 18 to 20% for AKI with the need for RRT. In our study encompassing mechanically-ventilated COVID-19 patients, we observed an equivalent incidence of AKI, although the percentage of patients who received RRT was lower. The latter may be partially explained by the exclusion of patients with advanced CKD and those with a kidney transplant. Acute kidney injury in COVID-19 has been associated with the use of high positive pressure ventilation [25], although it is not known if this observation is explained by a direct effect of positive pressure ventilation (which can reduce kidney perfusion and glomerular filtration [26]), or the fact that high-pressure ventilation may be a marker for sicker patients.
Several other risk factors are associated with AKI in COVID-19, including age, laboratory parameters, interventions such as vasopressors and IMV, and severity scores (SOFA, APACHE-II) [20, 21, 23, 27–29]. Consistent with the previous reports, we observed an association between increasing age and body mass index, laboratory parameters as glucose and LDH, and vasopressor use with the development of severe AKI.
Noteworthy, we observed that a protocolized dexamethasone regimen was associated with lower development of AKI in mechanically-ventilated COVID-19 patients after adjustment for the risk factors described above. Previous small reports suggested an effect of glucocorticoid treatment on AKI in COVID-19. Lowe et al [9], described a lower incidence of AKI in a cohort of 81 critically ill COVID-19 patients treated with glucocorticoids. Moreover, Lumlertgul et al [10] observed less AKI progression in subjects treated with glucocorticoids in adjusted analyses. Pineiro et al [11] reported less AKI with RRT requirement in those treated with glucocorticoids. These initial reports suggested a potential beneficial effect of glucocorticoid treatment in AKI development; however, they were limited by the small number of patients included and the non-protocolized use of glucocorticoids. In the RECOVERY trial [8], the number of patients who received RRT was lower in those treated with a protocolized dexamethasone regimen. A recent report from France [12] included 100 critically ill COVID-19 patients and where DXM was administered to all patients during the second COVID-19 wave, DXM use was associated with less AKI in the adjusted analysis (OR=0.31, 95%CI 0.09-0.99). Here, in a larger population and a protocolized DXM regimen, we ascertained that DXM treatment is associated with a 66% (95%CI 48-88%) lower incidence of severe AKI.
Acute kidney injury is a well-recognized factor associated with mortality in critically-ill COVID-19 patients [5, 21, 27, 30], therefore, any intervention that decreases AKI incidence would be expected to also decrease patient mortality. As previously demonstrated in the RECOVERY trial and verified in subsequent studies [8, 31, 32], DXM treatment reduces mortality in COVID-19 patients with oxygen requirement, including those undergoing IMV. In this study, we showed that DXM treatment is associated with a reduced mortality in patients with severe AKI, as well as in the group of patients without severe AKI, after adjustment for other risk factors.
Glucocorticoids have been widely used in septic shock and ARDS, given the central role of the inflammatory cascade in the pathogenesis of these diseases. They have also been used in other viral diseases, such as MERS, SARS, and influenza [33–35]. Nonetheless, the evidence for their efficacy in the management of these diseases has been inconclusive, without a clear definition for dosing, the timing of implementation, and a lack of randomized controlled trials. In the RECOVERY trial [8], DXM was started during the second week of the clinical course of COVID-19, a stage where inflammation plays a determinant role and where the SARS-CoV-2 viral replication may be less relevant. Several cytokines have been associated with AKI in COVID-19, including interleukin (IL) -1, IL-6, interferon-gamma, tumor necrosis factor-alpha; and inflammatory pathways such as the complement pathway have been linked to kidney damage [36]. Therefore, a direct effect of glucocorticoids on inflammation and the consequent improvement in kidney microcirculatory function may aid prevent the development of AKI in COVID-19. Of course, several other mechanisms may be involved, as the effect of DXM in reducing disease severity and other organic failures may be directly associated with less kidney injury.
Finally, it has also been reported that DXM treatment reduces the length of days under IMV and the length of hospitalization [11, 18, 19, 37]. We also observed a reduction in these parameters consistent with these studies, although they were not affected by DXM treatment. Renal recovery was observed in most surviving patients after RRT, with or without DXM treatment. This high percentage is higher than that observed in other series [21, 37, 38] and possibly influenced by the exclusion of patients with advanced previous kidney damage. Still, the serum creatinine-based definition for recovery of kidney function does not account for the loss of the renal reserve and should be taken cautiously as it has been reported that COVID-19 survivors have a higher risk of eGFR decline, end-stage kidney disease, and major adverse kidney events [39].
There are limitations to this study. As an observational study, some factors associated with AKI development may have not been registered. Therefore, the association between DXM treatment and AKI prevention may be overestimated and it is not possible to establish a causal role. The study did not account for differences in AKI incidence and mortality according to the COVID-19 pandemic waves at our center and the time from the start of the pandemic.