Abstract
Objectives: Although acute respiratory syndrome is the main manifestation of COVID-19 disease, one of the characteristics of the disease is acute kidney injury (AKI). This study aimed to assess the prevalence of kidney dysfunction and para-clinical outcomes in hospitalized COVID-19 patients and its relationship with mortality.
Methods: This cross-sectional analytical study was carried out on 715 patients aged older than 16-years with a diagnosis of COVID-19 admitted to the tertiary teaching Imam Reza Hospital, Mashhad, Iran from February 2020 to February 2021. During hospitalization, these patients were evaluated for AKI based on the Kidney Disease Improving Global Outcomes classification and mortality. Demographic variables and laboratory data were extracted from the hospital information systems electronic database. The significant risk factors for the incidence of AKI were analyzed using SPSS software in the present study.
Results: The mortality rate of the included patients was 18.9%, which expired during hospitalization. Mortality was higher among patients with stage 1-2 AKI (34.1%) and stage 3 AKI (44.9%) compared to patients without AKI (8.7%). Individuals in different stages of AKI were significantly older relative to the non-AKI patients; hence, aging could be considered as the predictor of AKI. Leukocytosis, lactate dehydrogenase (LDH), and blood urea nitrogen (BUN) were indicated as significant risk factors for the incidence of AKI.
Conclusions: It was found that the prevalence of AKI was 37.2% in hospitalized COVID-19 patients, and there was an association between mortality and the incidence of AKI.
The COVID-19 disease can present with pulmonary and extrapulmonary manifestations. One of the common complications caused by this disease is acute kidney injury (AKI).1 The causes of kidney involvement in COVID-19 are multifactorial. Evidence shows the kidney can be a target for this novel virus.2 In general, the mechanisms of renal involvement in these patients can be divided into cytokine damage, cross-organ dysfunction, and systemic effects. Some factors, such as cardiovascular disease, as well as predisposing factors, such as sepsis, hypovolemia, and nephrotoxins are important in this field. Autopsy data show the endothelium in the lungs and kidneys is affected and causes proteinuria in the kidney.3 Blood urea nitrogen (BUN) was elevated in 27% of all patients and in two-thirds of patients who died.4
In the more advanced stages of COVID-19 disease, acute renal failure is more common. The results of recent studies have shown renal abnormality, ranging between 1% and 42% in COVID-19 patients.5 Acute renal failure affects 46% of hospitalized patients.5 In comparison with patients in the intensive care unit (ICU), the percentage of mortality of patients with AKI is about 42%, which is significantly higher than those without AKI, which is about 7%.5 Therefore, AKI is a marker for a negative prognostic factor used to predict the severity of the disease and the development of multiple organ failure.5,6
The severity of AKI in COVID-19 in the early stages of hospitalization may be underestimated, because creatinine levels at admission may not reflect primary renal function before admission. Besides that, previous serum creatinine levels may not be available. According to research on COVID-19 patients, although renal impairment started before the onset of severe respiratory symptoms, the severity of respiratory failure was an independent risk factor for renal failure and increased mortality in these patients.4,7,8 Therefore, to reduce mortality and morbidity, it is necessary to recognize renal involvement in COVID-19 early and use preventive and therapeutic methods to limit the development of new cases of acute renal failure or progression to higher intensities. The identification of factors that predict a negative outcome is key to improving survival from COVID-19.4,9 We conducted the present study to investigate the incidence, severity, risk factors, and outcomes associated with AKI in hospitalized COVID-19 patients, due to the lack of studies on the incidence and severity of AKI in Iranian COVID-19 patients.
Materials and Methods
Study Population
The present cross-sectional analytical study aimed to evaluate the status of AKI in COVID-19 patients admitted to the tertiary teaching Imam Reza Hospital, Mashhad, Iran as the referral center for COVID-19 patients in the metropolitan city of Mashhad. A systematic random selection technique was used to identify 715 patients. In this study, patients’ records were received from the hospital information system. This routine database study achieved the approval of the Ethics Committee of Mashhad University of Medical Sciences, Mashhad (IR. MUMS.fm.REC.1396.499) to evaluate patients admitted due to COVID-19.
Inclusion and Exclusion Criteria
The hospitalized COVID-19 patients older than age 16 years and lacking a history of renal dysfunction, end-stage renal disease, and kidney transplantation who were admitted to the tertiary teaching Imam Reza Hospital, Mashhad, Iran, between February 2020 and February 2021 were included in this study. These patients had a laboratory-confirmed result of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and were admitted to the hospital. A confirmed case of COVID-19 was defined by a positive reverse transcription-polymerase chain reaction (PCR) assay of a specimen collected via nasopharyngeal swab. Lack of a history of renal dysfunction, kidney transplantation, or end-stage renal failure was extracted from each patient’s hospital file, which is based on the clinical and para-clinical findings of patients who were approved by nephrologists. Patients who lacked sufficient laboratory data or were transferred to other hospitals were excluded from the study.
Data Collection
We obtained demographic information of patients including age, gender, and laboratory data during hospitalization. The basic laboratory investigation included serum creatinine, urea, complete blood count, liver function test, albumin, serum lactate dehydrogenase and inflammatory factors, and geometrical analyses (changes such as oxygen level, carbon dioxide, and bicarbonate), ionomeric analyses (sodium, potassium, and calcium levels), and pH were carried out for all patients at the first day and last time of admission during hospitalization. Following that, sampling was performed based on the daily request of the treating physician.
Measurement Methods
During hospitalization, these patients were evaluated for AKI. To define and categorize the severity of AKI, recently Kidney Disease Improving Global Outcomes (KDIGO) criteria have the greatest applicability in epidemiologic studies.11 Therefore, the presence or absence of acute renal failure in these patients was determined based on these criteria. When a previous serum creatinine for patients 7 to 365 days before admission was known, the most recent serum creatinine value was considered the baseline creatinine.
Using KDIGO, AKI stages were defined. Accordingly, stage 1 is determined as an increase in serum creatinine of 0.3 mg/dl or an increase to 1.5-1.9 times as baseline serum creatinine, stage 2 as an increase to 2-2.9 times as baseline serum creatinine, and stage 3 as an increase to more than 3 times as baseline serum creatinine, a peak serum creatinine of 4.0 mg/dl, or if the patient received hemodialysis during admission. In this study, the classification of patients based on AKI was performed as follows: patients without AKI (with creatinine <1.3 mg/dl), patients with degrees of AKI (with creatinine between 1.3 and 4 mg/dl), and finally patients with severe AKI or stage 3 KDIGO (with creatinine >4 mg/dl). We could not measure the proteinuria or protein-creatinine ratio, leukocyturia, and hematuria in our study, because physicians rarely order urine analysis; therefore, these data were not available. Urine output was not used as a criterion of AKI in our study due to the lack of regular urine collection of patients in the ward and the use of diuretics in these patients.
Statistical Analyses
Data analysis was performed in SPSS software (version 20.0). The continuous variables with normal or non-normal distribution were reported as the mean ± standard deviation (SD) or median (percentile 25-75), and the normal distribution of data was determined using the Kolmogorov-Smirnov test. The frequency and percentage were expressed to describe qualitative variables and analyzed using Chi-square or Fisher’s exact tests. The one-way ANOVA or Kruskal-Wallis test was utilized to compare the continuous variables among non-AKI, AKI stage 1-2, and AKI stage 3 groups. Additionally, the comparison of continuous variables within each group was accomplished using the paired sample t-test or Wilcoxon test. The logistic regression model was used to evaluate the effect of significant independent variables on the incidence of AKI and the odds ratio (OR), and 95% confidence intervals (CI) were reported. The significance level was set at P<0.05.
Results
Participants in this study included 715 hospitalized patients with positive SARS-CoV-2 PCR tests who fulfilled our inclusion and exclusion criteria. Overall, 263 (36.8%) women and 452 (63.2%) men were recruited for the study. The mean age of the patients was 59.5±16.7 years, and the overall age range of the patients varied from 16 to 97 years. Of these, 135 (18.9%) patients died, while 488 (68.3%) patients recovered, and the conditions of 92 COVID-19 patients were not known in this study regarding the recovery or mortality status. The live or expired status of the mentioned patients had not been registered in the hospital file of patients and could not be followed.
Demographic features and recovery status of patients stratified by AKI, including non-AKI, AKI stages 1-2, and AKI stage 3 groups are displayed in Table 1. According to the classification of the prevalence of AKI in our study, out of 715 COVID-19 patients, 449 (62.8%) cases lacked AKI, while 266 (37.2%) cases had AKI in the classification. Patients who developed AKI were significantly older compared to COVID-19 patients without AKI (P<0.001). Additionally, the frequency of male patients was significantly higher than women in all groups (P=0.001).
Demographic characteristics and recovery status of COVID-19 patients based on AKI.
The frequency of males in AKI (stages 1-3) and non-AKI patients was 165 (42.1%), and 227 (57.9%) respectively. The frequency of females was 64 (27.7%) in AKI individuals, while the mentioned frequency was 167 (72.3%) in the non-AKI group. Significant differences were found based on gender between non-AKI and AKI (stage 1-3) groups (P<0.001). Moreover, The frequency of females and males was 51 (79.7%), and 138 (83.6%) in AKI patients with stages 1-2, respectively, and patients with stage 3 AKI included 13 (20.3%) females, and 27 (16.4%) males, with no significance between-group differences (P=0.480).
Among the patients, 217 (30.3%) patients had stages 1 and 2 AKI, based on KDIGO criteria with a mortality rate of 34.1%; whereas, the stage 3 AKI group consisted of 49 (6.9%) subjects, with a mortality rate of 44.9%. The recovery and mortality rates of 449 patients without AKI were determined at 79.1%, and 8.7%, respectively. A significant increasing trend was observed in the mortality status of AKI patients compared to the non-AKI group (P<0.001).
The comparison of clinical and laboratory features based on various stages of AKI in COVID-19 patients is presented in Table 2. Significant differences were found in terms of creatinine and BUN serum levels among three AKI groups at baseline admission (P<0.001) and maximum levels (P<0.001) during hospitalization with no statistical significance within each group. The trend of mean creatinine levels on different days of patients’ hospitalization is shown in Figure 1. The results revealed there were significant differences in creatinine levels among the three groups from baseline till the seventh day of hospitalization (P≤0.001), while after that, significant differences were present between non-AKI or AKI stage 1-2 groups on the one hand, and hospitalized patients with stage 3 AKI on the other.
The mean levels of creatinine in the non-AKI group, AKI stage 1-2, and AKI stage 3 during hospitalization.
Comparison of clinical and laboratory findings based on different stages of AKI in COVID-19 patients.
According to Table 2, the lactate dehydrogenase (LDH) inflammatory marker was statistically significant at the baseline (P=0.002) and the highest measured values (P<0.001) among AKI groups, whereas the C-reactive protein (CRP) was significant at the baseline of admission (P<0.001).
The results of the arterial blood gas test analysis revealed a statistical significance in terms of partial pressure of oxygen in the arterial blood (PaO2) levels among patients with different degrees of AKI at the baseline and endpoint of admission. In this study, regarding liver function tests in COVID-19 patients with AKI, levels of alkaline phosphatase were significantly higher compared to others without AKI at the baseline (P<0.001) and endpoint (P=0.003).
Patients who developed AKI and had severe AKI had significantly higher white blood cell (WBC) counts (P<0.001), lower lymphocyte percentages (P<0.001), higher neutrophil (P<0.001), and lower amounts of platelets (P≤0.010), and hemoglobin (P<0.001) compared to the non-AKI group at the baseline and endpoint of admission. Table 3 demonstrates BUN (OR=1.144, 95% CI=1.064-1.230), WBC (OR=1.318, 95% CI=1.037-1.675), and LDH (OR=1.003, 95% CI=1.000-1.006) were the significant risk factors on the incidence of AKI based on the logistic regression model.
The assessment of significant risk factors on the incidence of AKI using a logistic regression model.
Discussion
In the present study, 715 patients with COVID-19 were admitted to the hospital; AKI occurred in almost one-third of patients (37.2%). COVID-19 patients with AKI had a significantly higher level of BUN, creatinine, LDH, C-reactive protein, alkaline phosphatase, potassium, phosphorous, WBC, and neutrophil, as well as lower pH, HCO3 (bicarbonate), hemoglobin, platelet, and lymphocyte in comparison to patients without AKI during hospitalization. Among the laboratory variables, LDH, BUN, and WBC were independently associated with a high risk of AKI.
AKI is the second leading cause of mortality and morbidity in these patients.10,11 In one study, the incidence of AKI in the first 45 days of COVID-19 disease was 17.2%. Pre-renal and sepsis were the most common causes, respectively.12 In our study, 266 (37.2%) patients with COVID-19 experienced renal impairment. Patients with severe AKI had significantly higher levels of BUN and creatinine compared to patients without AKI.
Mortality
In the current study, patients with AKI had higher mortality and disease severity, and patients with higher stages of AKI based on KDIGO criteria had a higher mortality rate. Regarding, the mortality rate in the stage 3 AKI group, it was 44.9% in comparison patients without AKI (8.7%). On the other hand, recovery was higher among patients without AKI, at approximately 72.7%.
The results of our study were consistent with those of previous ones. In this regard, the findings of a study revealed mortality was 25% for the AKI group compared to 6.7% in those without AKI.11,13,14 Based on the results of another study, among ventilated critically ill adult patients with COVID-19, AKI occurred in 65.1%; therefore, in more severe patients, the prevalence of AKI was higher.14 AKI is an independent predictor of mortality and the development of multiple organ failure.5,6
Age and Gender
The results of our study revealed that the frequency of male patients was significantly higher in all AKI and in AKI patients with COVID-19. It was also found that patients in different stages of AKI were significantly older than patients without AKI; therefore, older age was considered a predictor of AKI, the same as the previous study.14
Electrolyte
Besides fluid overload, laboratory tests in AKI patients may reveal an imbalance in some electrolytes, such as hyperkalemia, hyponatremic, hypocalcemia, and hyperphosphatemia. As evidenced in other studies regarding potassium and phosphorous elements, the results of electrolytes in this study indicated patients with AKI had significantly higher amounts of potassium and phosphorous than their counterparts without AKI during hospitalization. It seems hyponatremia did not occur in the early stages of AKI in our patients.
In this study, the mean calcium levels were significantly decreased. Hypocalcemia has been reported as a common biochemical disorder in SARS, Ebola, and COVID-19 diseases.15 Given that vitamin D and calcium levels have been shown to have a direct relationship with the status of the immune system, while vitamin D deficiency has negative effects on it.16,17 It can be concluded that there is a direct relationship between hypocalcemia and the severity of the inflammatory response, the severity of the disease, and the increased risk of mortality.15,16
Arterial Blood Gas
Given that bicarbonate levels were low in tissue ischemia, AKI acidosis developed because hydrogen ions could not be excreted.12 According to our results, in people with more severe AKI, HCO3 and pH levels were significantly lower than in people without stages 1 and 2 AKI.
Inflammatory Factors
In our study, the relationship between CRP and LDH with the course of kidney damage was determined. The results of a previous study have shown there is a high incidence of acute renal impairment (approximately 81%) in critically ill adult patients with COVID-19, which has been associated with both CRP and high LDH.18-21 Patients who developed AKI during a hospital stay presented with higher LDH, D-dimer, and CRP values, more frequent ICU admission, renal replacement therapy requirement, and more severe pulmonary damage.22 In this study, no significant differences were observed in erythrocyte sedimentation rate (ESR) levels among AKI groups and without AKI nor within groups. However, ESR was considered a prognostic factor in COVID-19 patients.23
Complete Blood Count
Laboratory factors, such as high WBC counts, low blood platelet counts, decrease in lymphocyte count, and high blood neutrophil count are associated with prognosis and AKI in COVID-19 patients.13,23 Patients with higher degrees of AKI initially had significantly lower platelet counts. The findings of previous studies have shown the COVID-19 virus exacerbates inflammation in a series of specific platelet profiles, such as larger platelets.21
According to the results of other studies, patients with acute renal impairment had higher rates of neutrophil/lymphocyte, ferritin, lactate, and LDH levels18,19 than patients without AKI.20 The association of hemoglobin with the course of recovery and AKI was shown in our study. The results of one study showed a decrease in hemoglobin during hospitalization with COVID-19 had a higher risk of acute renal injury and nosocomial mortality.24
Liver Function Tests and Albumin
Liver injuries have been reported in patients with COVID-19 infection.25 The findings of some studies have shown that hepatic injury in severe COVID-19 patients may be caused by direct injury to the bile duct cells by a virus or indirectly by a cytokine storm.26 A retrospective analysis showed higher levels of aminotransferases, total bilirubin, and lactate dehydrogenase, as well as lower albumin, were observed in COVID-19 patients with severe/critical illness compared with mild/moderate ones.20 These factors are associated with worse prognosis and longer stays at the hospital.23,26 In the present study, the relationship of liver enzymes and total bilirubin levels with the course of the disease and AKI was significant.
Limitations, Strengths, and Weaknesses
The reason for the discrepancy between the results of previous studies and our findings was related to the fact that previous studies were performed in different geographical regions with different genetic backgrounds, ethnic groups, lifestyles, diets, and habits, while we evaluated Iranian patients. One of the limitations of our study was the lack of urine tests for the evaluation of proteinuria and the absence of basal creatinine for all patients. The other limitation of this study was that our study was conducted in only one center of treatment for COVID-19, and as a result, we had no access to the information in other medical centers. To balance this, a multicenter approach is required to promote the generalizability of the findings for managing patients in future pandemic situations such as COVID-19. In addition, we employed the regression model to evaluate the influencing variables in AKI incidence. However, it was not possible to determine a cause-and-effect relationship, because it was a cross-sectional study.
Suggestions for Further Research
It is recommended future studies be performed on a larger sample size in multicenter hospitals in several different geographical areas and races. These findings could present a broader perspective on how various populations are affected by AKI in COVID-19 infection. Moreover, it is suggested a longitudinal study of long-term follow-up of participants to evaluate the impact of AKI on renal function and mortality post-hospitalization due to COVID-19 be undertaken. In future studies, the basic creatinine of patients and urine analysis also need to be considered. Assessing the urine output in future studies could provide a more comprehensive assessment of AKI including AKI severity and staging. In addition, the impact of this infection on patients with chronic kidney disease and those on dialysis suspected to have COVID-19 was not studied. Evaluating proteinuria and other kidney markers could improve the comprehension of kidney injury mechanisms in COVID-19 infection.
Conclusion
The results of the present study showed AKI occurred with a high prevalence among patients with COVID-19, and mortality was higher among patients with AKI than other patients. We found patients with AKI were more likely to have liver function test impairment and had far more inflammatory factors, such as LDH, C-reacitve protein, ESR, and lower hemoglobin levels, platelets, and albumin levels compared to patients without AKI. Multiple measurements showed a significant increase in the amount of WBC (leukocytosis) and HCO3 (bicarbonate). The present findings revealed the essential of AKI early detection to manage COVID-19 patients. The potential benefits of this study could lead to better and more accurate planning to reduce the risk factors for COVID-19 disease in the study population and better management of patient treatment.
Acknowledgments
The authors’ deepest appreciation goes to the Vice-Chancellor for Research and Technology of Mashhad University of Medical Sciences for the provision of favorable conditions to conduct this research.
Footnotes
Disclosures: The authors declare that they have no conflict of interest related to the current article..
- Received August 14, 2024.
- Revision received October 27, 2024.
- Revision received November 25, 2024.
- Accepted November 26, 2024.
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