DISCUSSION
We compare laboratory finding for kidney and liver function between patients who were recovered from COVID-19 with the died patient during the same period. To our knowledge, this is the first study that has made such a comparison. Our goal was to investigate the possible cause of death other than respiratory failure for the patient with COVID-19.
Many studies conducted to investigate the risk factors for the development of AKI among COVID-19 patients. Old male gender (>50 years) have been confirmed to associated with a higher rate of AKI compared to young and female patients [13]. Another study concluded that increased ten years of age could be associated with a >10% increase in the risk of AKI [14]. Besides, other independent factors related to the development of AKI and mortality rate in COVID-19 patients include DM, hypertension, WBCs count, respiratory rate during disease episode, COPD, and previous history of chronic kidney diseases [15]. These were consistent with our result in which, died patients were older than recovered patient, and 76.09% were male. Meanwhile, the respiratory rate at admission was higher among died patient. The presence of COPD and hypertension could be the direct cause of death and the causative for AKI (Table 1).
Based on the previous researches and the wide spectrum of the involved mechanisms, COVID-19 patient with underlying AKI, indeed required mechanical ventilation and ICU admission and might prognoses with worse outcomes compared to healthy kidney patients [16]. In this study, all of them died patients were admitted to the ICU at least two days before death and died patients’ data were collected for this study a day before death was reported in the ICU.
Although patients with renal diseases have more risk for infection with COVID-19, patient infected by SARS-CoV-2 without a history of renal problems might opposite a burden for severe kidney injury and may progress to renal failure. Unfortunately, there was a less renal recovery in patients diagnosed with CVID-19 comparing to the patient with a negative result for COVID-19 [17]. Furthermore, COVID-19 patients with an advanced stage of AKI (Stage III and more) were reported to have more than 30% higher incidence for death compared to a patient with normal or subnormal kidney function [18]. Based on the previously mentioned facts, our result confirms that the renal function of died patients was ranged from normal to mild renal insufficiency at admission and then progressed to critical stage III and IV before death. Further, the non-significant difference in S.Cr level and eGFR between the died and recovered patients at admission and the progression of renal injury that is confirmed by spark elevation in S.Cr (>2.1 fold), BUN (> 62.2%) and reduction in eGFR (>62.3%) when we compare renal function test one day before death with the values obtained on admission. Altogether, these results indicate an association of AKI and mortality among COVID-19 patients (Table 2). Although studies showed a low rate of renal replacement therapy for COVID-19 patients with advanced AKI [19], this result explained by the high rate of mortality in advanced renal disease among patients suffering from SARS-CoV-2 infection. By this study, the risk of mortality in COVID-19 patients was strongly related to AKI (S.CR HR 44.23; 95% CI: 16.34, 119.70, p=0.000) and (BUN 13.04% versus 2.28%, HR 5.59, 95% CI: 1.86, 16.84, p=0.020) (Table 5, Fig. 3). In this regard, continuous monitoring of renal function with preventive and supportive therapies of renal disease is crucial for COVID-19 patients.
Another potential mechanism of AKI involves SARS-CoV-2 related cytokine storm that is related to immune response deregulations. It is a cytokine related systemic inflammatory response resulting in a variety of clinical manifestations such as uncontrolled high fever, CNS abnormalities, hepatic injury, lymphadenopathy and kidney toxicity related to the massive release of cytokines such as IFN-c, TNF, IL-1, IL6 and IL-18, and, if untreated progression to multiple organ failure (MOF) is almost inevitable [20]. Patient with cardiac comorbidity (particularly right ventricular failure secondary to COVID-19 pneumonia), or other predisposing factors for hypovolaemia, sepsis or nephrotoxicity; besides, macrophage activation syndrome, and the development of microemboli and microthrombi in the context of hypercoagulability and endotheliitis might lead to kidney and liver congestion and subsequent AKI and liver injury [21]. The results of this study confess the role of cytokine storm in the concurrent deterioration of renal and hepatic functions in COVID-19 patients death.
The liver biochemistry changed dynamically in patients infected by SARS-CoV-2 during the clinical course. ALT and total bilirubin founded to be an increase in 28% and 18%, respectively [22], in an early study in Wuhan, and 53% in a subsequent study [23]. The degree of acute liver injury was different in COVID-19 patients. The need for ICU was more prevalent in patient demonstrate high levels of ALT/AST, ALP and total bilirubin. Furthermore, the prevalence of abnormal liver biochemistry is high in COVID-19 patients at admission and increased during the disease course [24]. Importantly, these changes in hepatic parameters have a potential impact on COVID-19 patients and independently resulted in admission to ICU. Moreover, many studies showed that patients with the chronic hepatic disease were more liable to developed severe COVID-19 [25]. The previous facts are consistent with our results, in which only bilirubin was significantly higher at admission among died patients, whereas, just before death, extreme elevation in AST, ALT, and bilirubin were observed (Table 4, Fig. 2).
Studies were conducted and suggested that abnormal liver function can result from an infection of bile duct cells by SARS-CoV-2; however, alkaline phosphatase (ALP) founded not specific for COVID-19 patient as the bile duct injury-related index [26]. Interestingly, acute liver injury was believed to be due to the adverse drug reaction in patients using medication for the severe stage of COVID-19 [27]. Currently, many reports focus on the systemic inflammation that is associated with COVID-19 as a cause of liver injury [28]. These confirm our insights that cytokines storm could be the causative for kidney and liver injury with subsequent mortality in COVID-19 patients. Although the available data about the effect of a different antiviral drug on hepatic function, the use of corticosteroid in COVID-19 patients also seemed to induce acute hepatic injury [29]. This study was conducted to patients administered uniform protocol of therapy to exclude the effect of the drug on the results, taking into consideration the variability in the duration of therapy and doses used.
Even though no patients had recorded for short-term mortality due to liver injury, studies were focused on the role of regular hepatic biochemistry monitoring on hospitalization period and COVID-19 patients outcome [30]. More importantly, because of a large number of infected patients recorded daily worldwide, the effect of liver injury on COVID-19 patient outcomes is valuable, and its predictors can improve a patient’s health [3].
Therefore, in our study, besides AKI, we focused on the prognostic role of liver injury in COVID-19 patients and observed significant-high hepatic parameters indicative for liver injury among patient who are died.