Acute kidney injury (AKI) is a common complication in medical and surgical patients which carries a significant mortality association. From the Grampian Laboratory Outcomes Morbidity and Mortality Study II (GLOMMS-II), approximately 8–18% of hospitalized patients were diagnosed with AKI [1
]. Moreover, the incidence of AKI has increased correspondingly with the severity of illness. For example, a multi-national database indicated that AKI occurred in 22% of mechanically ventilated patients [2
]. Most of these patients developed AKI within two days after being admitted to the intensive care unit (ICU) [2
AKI is a well established risk factor for both in-hospital death as well as long-term mortality [1
]. By mitigating potential risk factors for AKI, clinicians could indirectly improve patients’ survival and quality of life. However, the knowledge on the pathophysiology and clinical impact of AKI in certain disease entities are limited, especially in emerging infectious diseases, such as coronavirus disease 2019 (COVID-19).
COVID-19 is a respiratory disease caused by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) which was first identified in Wuhan, China, in December 2019, before rapidly spreading to 216 countries, causing 18,142,718 infections, and 691,013 deaths as of 4 August 2020 [4
]. The highest disease burden was seen in the United States, bearing up to 26 and 22% of global confirmed cases and deaths, respectively [4
A recent meta-analysis has shown that the pooled incidence of AKI in COVID-19 was only 8.4% and its incidence was closely associated with an increased mortality rate [5
]. The incidence of AKI, however, could be as high as 20% in a recent cohort from the New York City area [6
]. Nevertheless, only a small number of studies to date have identified the risk factors for AKI in COVID-19. Hansrivijit et al. conducted a meta-analysis and described that age, diabetes, hypertension and baseline serum creatinine levels were potentially predictive factors for AKI in patients with COVID-19 [5
]. Furthermore, even fewer studies have reported the clinical or urine characteristics of COVID-19 patients who developed AKI. These data are essential in understanding the disease development as well as disease progression.
Hence, in this retrospective cohort study, we reviewed the incidence, risk factors, and clinical characteristics (blood chemistries and urine studies) of hospitalized COVID-19 patients with AKI. The knowledge obtained from this study would provide an insight on the clinical impact of SARS-CoV-2-associated AKI.
In the early stage of the pandemic, one meta-analysis reported the pooled incidence of AKI in COVID-19 at only 8.4% [13
]. However, most of their included studies were originated from China and used various diagnostic criteria to define AKI. In our study, the incidence of AKI accounted for up to 40% of patients. This number is almost double compared to the New York City metropolitan area [6
] and about eight-fold higher from what was originally reported in China [14
]. The data from the United Kingdom also reported 33.4% incidence of AKI with a significant association with death (OR 3.20; 95% CI 2.15–4.81) [15
]. In contrast, Lim et al. reported that only 18.3% of hospitalized Korean patients had AKI [16
]. By comparing our study, which is considered rural, to the data from the New York City metropolitan area, the discrepancy in the incidence of AKI could be explained by the difference in patient population and racial distribution. Our patients were generally older, Caucasian race, with a higher prevalence of diabetes and CKD. Moreover, residents of nursing homes constituted a significant proportion of our patient population. Not surprisingly, our reported incidence of AKI is similar to a cohort of 13 rural hospitals in the New York Heath System located outside of New York City where most patients reside in long-term living facilities [17
]. With this evidence, it is suggested that the incidence of AKI varies by location and region, that is, rural population may have a higher incidence of AKI. Moreover, our study also suggested that most AKIs were community-acquired, and pre-renal in nature, which could be associated with dehydration and poor oral intake, especially in the elderly population. Additional studies comparing the incidence of AKI between the metropolitan area and rural area are needed to confirm our speculation.
The most common etiology among all causes of AKI was pre-renal (70.4%; 81/115) and intrinsic (34.8%; 40/115). Most community-acquired AKIs were due to pre-renal origin while most hospital-acquired AKI were intrinsic. The need for RRT was significantly higher in hospital-acquired and intrinsic AKI. We also confirmed the impact of AKI on the overall mortality, regardless of AKI etiology. Both pre-renal and intrinsic AKI were significantly associated with increased death from COVID-19.
Death was significantly more common in patients with hospital-acquired AKI and in patients with intrinsic AKI. Patients who developed AKI in the hospital tended to be more complicated and critically ill. Multiorgan failure other than the kidneys could also contribute to the higher mortality rate. In addition, we also found that renal replacement therapy was more common in intrinsic AKI. However, we adjusted the association between AKI and death with other co-variates including age, sex, ethnicity, diabetes, hypertension and CKD to minimize confounding bias.
In one meta-regression analysis, increasing age, diabetes, hypertension, and elevated baseline serum creatinine levels were positively associated with AKI [5
]. Similarly, the data from South Korea showed that ARDS and low serum albumin on admission were independent risk factors for AKI [16
]. Such findings emphasized the importance of defining the risk factors for AKI in these patients in order to prevent death from COVID-19.
We identified several risk factors associated with AKI. In brief, the risk factors of AKI in COVID-19 can be divided into six categories: (1) demographics/co-morbidities (male, age, diabetes, chronic kidney disease); (2) possible liver and cardiac involvement (transaminitis, elevated troponin I, ST-T change on EKG); (3) elevated biomarkers (ferritin, LDH); (4) possible bacterial co-infection (leukocytosis, procalcitonin); (5) the need for advanced oxygen delivery (non-invasive positive pressure ventilation (NIPPV), mechanical ventilation); and (6) other critical features (respiratory acidosis, ICU admission, need for vasopressor, ARDS). Most of these risk factors are consistent with a retrospective cohort from New York Heath System [17
] and undoubtedly similar to the data from non-COVID-19 patients [18
Our findings confirm the risk factors that were identified in previous studies. Age, diabetes, hypertension, and CKD are well known risk factors even in general non-COVID-19 patients. Our findings are also in line with the risk factors reported by the recent meta-analysis [5
]. Acute respiratory distress syndrome was also reported as a mutual risk factor in our cohort and in Lim et al. [16
]. However, unlike Lim et al., our current study did not examine the effect of serum albumin levels. The significance of hypoalbuminemia toward AKI occurrence has been demonstrated in the literature. A meta-analysis of 168,740 subjects concluded that each 1.0 g/dL decrement of serum albumin levels was associated with a 1.7-fold increased risk of AKI [13
]. Although we have identified 17 risk factors for AKI, we believe that there are more potential risk factors for AKI that need to be investigated in the future studies.
The cytokine storm characterized by unregulated proinflammatory cytokine production and excessive cytokine release in response to SARS-CoV-2 infection is a hallmark of clinical deterioration and death from COVID-19 [19
]. This immunologic response is mediated by several cytokines including IL-1, IL-2, IL-6, IFN-γ. Ferritin, D-dimer and LDH are indirect inflammatory markers and have been recognized as predictive factors for severe COVID-19 and disease progression [21
]. With our data, elevated ferritin and LDH could be used as surrogate markers for the risk of AKI as well. Additionally, the presence of transaminitis and elevated troponin I could indicate liver and cardiac involvement resulting from COVID-19 progression, which corresponded with elevated inflammatory biomarkers. In brief, one could conclude that elevated biomarkers caused by COVID-19 are associated with multiple organ involvement which carries a significant mortality. Moreover, elevated procalcitonin and leukocytosis could indicate superimposed bacterial infection which impact the survival from COVID-19. It is speculated that patients with superimposed bacterial infection are more severely ill and would have higher probability of developing AKI.
It is known that the incidence of AKI surges in mechanically ventilated patients. Hirsh et al. described that severe AKI occurred most commonly in close temporal proximity to the time of intubation [17
]. Here, we added that advanced oxygen delivery, including NIPPV, was also associated with AKI. Although AKI could result from worsening respiratory failure and distant organ involvement as mentioned above, there is substantial evidence suggesting a direct connection between mechanical ventilation and AKI. Positive pressure ventilation could result in micro-stretching of the alveoli, resulting in proinflammatory cytokine release and the stimulation of renin–angiotensin system that eventually alter the renal perfusion [22
]. However, more animal studies are encouraged to confirm such findings.
Male, stage 3 AKI, higher baseline serum creatinine, peak serum creatinine and BUN were suggestive of AKI due to intrinsic causes. The pathogenesis of AKI in COVID-19 has not been fully elucidated. Although ischemic acute tubular necrosis (ATN) often occurs in the setting of circulatory collapse and several infections, the systemic prothrombotic state associated with COVID-19 could result in thrombotic microangiopathy of the kidneys. Similar to Hirsch et al. [17
], our results showed that urine analysis and urine chemistry, such as FE-sodium and FE-urea, are not helpful in distinguishing between intrinsic AKI from other causes of AKI, as both entities had FE-Na and FE-urea less than 1 and 35%, respectively. Although these findings are traditionally indicative of pre-renal state, glomerulonephritis or certain forms of ATN could give the same results.
The question remains, “Does SARS-CoV-2 directly involve the kidneys?
” A recent important datum derived from post-mortem kidney biopsies has shown that the most common pathologic diagnosis in patients who died from COVID-19 was acute tubular injury with focal acute tubular necrosis [24
]. Thrombotic microangiopathy or other glomerular manifestations were not observed. Immunohistochemical assays from SARS-CoV-2 nucleocapsid protein were negative in all patients suggesting no direct evidence of viral infection in the kidneys [24
]. However, these findings are contradictory to the previous study from China. Su et al. found clusters of coronavirus-like particles in the tubular epithelium and podocytes along with positive immunostaining with SARS-CoV-2 nucleoprotein antibody and suggested that SARS-CoV-2 could directly infect the renal tubular cells [26
]. Taken together, although it is possible that the absence of viral particles in the renal tubules from Santoriello et al. [24
] and Golmai et al. [25
] could be explained by post-mortem RNA degradation, a concept of direct renal tubules infiltration by SARS-CoV-2 needs to be revisited once more data are available.
Our study is among the earliest studies to entail the clinical characteristics and significance of AKI in COVID-19 from a racially diverse population. However, some limitations should be noted. The small sample size of our study remains the major limitation. The hospitalization criteria were not identified specifically for each hospitalized patient. Thus, comparing the difference between hospitalized and non-hospitalized groups might not be practical. Although intrinsic AKI was diagnosed using established criteria, there was, however, no confirmation kidney biopsy. Moreover, the microscopy of the urine was not performed according to the hospital policy to prevent SARS-CoV-2 exposure among technicians. FE-Na, FE-urea, and urine analysis were not available in all patients with AKI which might reduce the robusticity of the analysis. Furthermore, at the beginning of the pandemic, RRT was underperformed at our institution due to bed capacity and staff shortage. As a result, the analysis of predictive factors for RRT cannot be performed due to the small sample size of patients who received RRT.