The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), known as the cause of coronavirus disease 2019 (COVID-19), was first identified in Wuhan, China in December 2019. The emergence of this virus has led to a global pandemic, affecting millions of individuals worldwide. The presentation of COVID-19 varies widely among different populations, including children. In some cases, the disease can be asymptomatic, meaning the individual shows no symptoms at all. In other cases, symptoms may be mild and confined to the respiratory system, such as coughing and difficulty breathing, or the gastrointestinal system, such as diarrhea and vomiting. However, COVID-19 can also cause severe illness affecting multiple organs, including the kidneys.
There is growing evidence that the kidneys are a target organ for SARS-CoV-2. The virus attaches to a specific receptor called the angiotensin-converting enzyme 2 (ACE2) receptor, which is found in high amounts on certain kidney cells, specifically renal tubular cells and podocytes. When the virus binds to these receptors, it can cause direct damage to the kidneys. Acute kidney injury (AKI) has been identified as a significant complication of COVID-19 and is associated with the severity and outcome of the disease. AKI is a sudden decrease in kidney function that can range from mild to severe and is a risk factor for poor outcomes in both children and adults infected with COVID-19.
The incidence of AKI in children with COVID-19 varies widely, with reports ranging from 0% to 70%. This wide range is likely due to differences in the populations studied and the criteria used to define AKI. Despite the growing number of studies, there are limited data regarding the specific risk factors and potential outcomes associated with AKI in children with COVID-19. Some studies have suggested that exposure to nephrotoxic drugs, high levels of C-reactive protein (CRP), increased white blood cell (WBC) counts, and low serum albumin levels may be risk factors for developing AKI in pediatric COVID-19 patients. The inflammatory state caused by the infection itself may also contribute to renal hypoperfusion, a condition where the kidneys receive less blood flow, leading to AKI.
Understanding the frequency of AKI and identifying risk factors in children with COVID-19 is crucial for guiding the treatment of these patients. While some risk factors for AKI have been reported in hospitalized patients, it remains unclear whether the same factors apply to outpatients, who may have different characteristics and underlying health conditions.
This study aims to describe the risk factors for AKI in both hospitalized and outpatient pediatric COVID-19 patients and determine whether previously known risk factors contribute to AKI associated with COVID-19. By examining a large population of children with confirmed COVID-19 infections, this study seeks to provide a comprehensive analysis of the incidence, risk factors, and outcomes of AKI in this vulnerable population.
To achieve this goal, a retrospective observational study was conducted at a tertiary pediatric referral hospital. The study included 6683 children with a polymerase chain reaction (PCR)-confirmed diagnosis of COVID-19 who were admitted to the hospital’s COVID-19 polyclinic or emergency department from March 1, 2020, to March 1, 2022. Among these patients, serum creatinine values were evaluated in 486 individuals due to their clinical conditions, and these patients were included in the study.
Data were collected from hospital electronic records and included information on demographics, clinical characteristics, laboratory findings, radiologic investigations, hospital stay, and medication use during hospitalization. The patients were divided into two groups: those with AKI and those without AKI. Various parameters were recorded, including baseline and peak serum creatinine levels, baseline and lowest estimated glomerular filtration rate (eGFR), kidney and liver function tests, electrolytes, blood urea nitrogen (BUN), serum albumin, lactate dehydrogenase (LDH), complete blood count, CRP, ferritin, creatine kinase (CK), d-dimer, troponin values, urine dipstick tests, urine output, urine culture, and blood culture. Imaging studies, such as echocardiography (ECHO), chest X-ray, and computed tomography (CT), were performed when indicated.
There have been relatively few studies focusing on AKI in children with COVID-19. While a high incidence of AKI has been reported as a prominent feature in adult COVID-19 patients, the incidence in children appears to be lower. One retrospective study conducted in China on 238 pediatric hospitalized patients and outpatients reported AKI in only 3 patients (1.2%), a rate much lower than those reported in studies from the United States (24%) and the United Kingdom (29%). A meta-analysis found that 44% of critically ill children developed AKI according to the KDIGO serum creatinine criteria. The discrepancies in the frequency of COVID-19-associated AKI among different countries and studies may be due to variations in inclusion criteria, such as age, severity of illness, whether the patients were hospitalized or outpatients, intensive care admissions, and different definitions of AKI.
Conflicting results have been reported regarding the role of comorbidities in the development and severity of AKI in COVID-19 patients. In general, the presence of comorbidities, such as respiratory diseases, cardiac diseases, hematological disorders, and malignancies, is associated with increased severity of AKI in children with COVID-19. A systematic review reported that 26.7% of children with AKI had underlying comorbidities. In this study, a similar prevalence of comorbidities was observed (28.6%), with 52.5% of patients with AKI having underlying diseases. Compared to adults, pediatric patients with COVID-19 and AKI had a lower prevalence of comorbidities and different types of comorbid conditions.
Several mechanisms may contribute to kidney injury during COVID-19 infection, including direct infection of kidney cells by the virus, damage to blood vessels, ischemic acute tubular necrosis, imbalances in the renin-angiotensin-aldosterone system, microthrombosis (small blood clots), increased vascular permeability (leakiness of blood vessels), and volume depletion (dehydration). Additionally, kidney damage can occur secondary to hemodynamic instability, inflammatory cytokines (proteins involved in inflammation), and therapeutic approaches such as the use of nephrotoxic medications and mechanical ventilation.
The present study confirmed that AKI was a risk factor for admission to the hospital and the pediatric intensive care unit (PICU), and that patients with AKI were more likely to require longer hospital stays. This association between AKI and hospital length of stay has also been reported by other pediatric studies. The need for mechanical ventilation and the use of multiple medications were common among AKI patients in this study, consistent with findings in seriously ill children with AKI. Early identification and supportive therapy for AKI may help improve outcomes for pediatric COVID-19 patients.
Acute kidney injury has a significant impact on mortality in COVID-19 patients. Higher stages of AKI are associated with greater mortality, and COVID-19 patients with AKI have a significantly higher risk of death compared to those without AKI. In this study, the mortality rate among COVID-19-positive patients was 1.4%, lower than the AKI mortality rate of 3.3% reported in the literature.
The study has several limitations. A baseline serum creatinine measurement was unavailable for most COVID-19 patients, as they were previously healthy. The observational nature of the study means that some information on serum creatinine levels could not be retrieved, potentially leading to under-reporting of AKI diagnoses. Additionally, only PCR-positive confirmed COVID-19 patients were included, which may have missed asymptomatic or mildly symptomatic patients treated at home. Despite these limitations, the study’s strength lies in the inclusion of AKI patients in both outpatient and inpatient settings.
In conclusion, AKI was diagnosed in 3.7% of outpatients and 23.9% of hospitalized pediatric patients with COVID-19. The study highlights that children with higher levels of inflammation markers, particularly a higher neutrophil-to-lymphocyte ratio (NLR) and lower serum albumin levels on admission, may be more prone to developing COVID-19-associated AKI. Pediatric COVID-19 patients with AKI requiring hospitalization had more admissions to the PICU, longer hospital stays, and a greater need for mechanical ventilation compared to those without AKI. Given the link between COVID-19-associated AKI and both mortality and poor prognosis, it is crucial to closely monitor renal function in children with COVID-19.
The Study ….
The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), known as the cause of coronavirus disease 2019 (COVID-19), was first identified in Wuhan, China in December 2019 [1]. The presentation of COVID-19 varies widely, ranging from an asymptomatic response to isolated respiratory and/or gastrointestinal symptoms, or to the development of multiorgan systemic disease [2]. There is evidence that the kidney is a target organ for SARS-CoV-2, and that the highly expressed angiotensin-converting enzyme 2 receptor on renal tubular cells and podocytes are required for SARS [3].
Acute kidney injury (AKI) is associated with COVID-19 severity and outcome and seems to be a risk factor for adverse outcomes among both outpatients and hospitalized children [1, 4]. The reported incidence of AKI in children with COVID-19 ranges from 0 to 70% [5]. There are limited data regarding AKI-associated risk factors and potential outcomes in children with COVID-19. It has been reported that exposure to nephrotoxic drugs, high C-reactive protein (CRP), increased white blood cell (WBC) counts, and low serum albumin levels may be risk factors for AKI in children with COVID-19 [2, 3, 6]. The inflammatory state itself may be a manifestation of COVID-19 infection that predisposes to renal hypoperfusion and AKI. Despite these data, the risk factors and potential outcomes of AKI associated with COVID-19 in pediatric patients are not well defined. Estimation of the frequency of AKI and identification of risk factors in children with COVID-19 remain essential to guide the treatment of these patients. Although risk factors for AKI have been reported in hospitalized patients, the factors for identifying patients at high risk of AKI in outpatient settings are unknown and may differ from those recorded in hospitalized children.
This study aimed to describe risk factors for AKI in both hospitalized and outpatient pediatric COVID-19 patients and determine if previously known risk factors contribute to AKI associated with COVID-19.
Patients and Data Collection
In this retrospective observational study, 6683 children with a polymerase chain reaction (PCR)-confirmed diagnosis of COVID-19 infection admitted to the COVID-19 polyclinic or emergency department of a tertiary pediatric referral hospital from March 1, 2020, to March 1, 2022, were selected. Among them, serum creatinine values were evaluated in 486 patients due to their clinical conditions, and they were included in the study. Data regarding demographics and clinical characteristics, laboratory findings, radiologic investigations, hospital stay, and medication use during hospitalization were collected from the hospital electronic records. The patients were divided into two groups: AKI and non-AKI.
Baseline and peak serum creatinine levels, baseline and the lowest estimated glomerular filtration rate (eGFR), kidney and liver function tests, electrolytes, serum levels of blood urea nitrogen (BUN), serum albumin, lactate dehydrogenase (LDH), complete blood count, the highest CRP, ferritin, creatine kinase (CK), d-dimer, troponin values, and urine dipstick tests, urine output (UOP), urine culture, and blood culture were recorded (if available). Echocardiography (ECHO), chest X-ray, and computed tomography were performed when indicated.
Table Outline for Key Concepts in Pediatric COVID-19 and Acute Kidney Injury (AKI)
| Concept | Explanation |
|---|---|
| SARS-CoV-2 | The virus that causes COVID-19, first identified in Wuhan, China in December 2019. |
| COVID-19 | A disease caused by the SARS-CoV-2 virus. Symptoms range from no symptoms at all to severe illness affecting many organs in the body. |
| Acute Kidney Injury (AKI) | A sudden loss of kidney function, which can range from mild to severe. The kidneys are less able to filter waste from the blood. |
| Pediatric Patients | Refers to children and adolescents. |
| Polymerase Chain Reaction (PCR) | A test used to detect the presence of the virus that causes COVID-19 by finding its genetic material in a sample taken from a patient. |
| Serum Creatinine | A waste product found in the blood that is normally filtered out by the kidneys. High levels can indicate poor kidney function. |
| Estimated Glomerular Filtration Rate (eGFR) | A measure of how well the kidneys are filtering waste from the blood. Lower numbers indicate worse kidney function. |
| C-Reactive Protein (CRP) | A substance produced by the liver in response to inflammation. Higher levels can indicate inflammation in the body. |
| White Blood Cells (WBC) | Cells in the blood that help fight infections. Higher counts can indicate an infection or inflammation. |
| Serum Albumin | A protein in the blood that helps keep fluid in the bloodstream. Low levels can indicate poor nutrition or inflammation. |
| Nephrotoxic Drugs | Medications that can cause damage to the kidneys. Examples include certain antibiotics and pain relievers. |
| Hemodynamic Instability | When blood pressure and blood flow are not stable, which can affect the function of organs, including the kidneys. |
| Proteinuria | The presence of protein in the urine, which can be a sign of kidney damage. |
| Comorbidities | The presence of one or more additional medical conditions co-occurring with a primary condition. For example, a child with COVID-19 may also have asthma or diabetes. |
| Inflammation Markers | Substances in the blood that indicate inflammation, such as CRP and ferritin. |
| Mechanical Ventilation | A machine that helps a person breathe when they are unable to do so on their own. Often used in severe cases of COVID-19. |
| Mortality Rate | The percentage of people who die from a particular disease or condition. |
| Systemic Inflammation | Widespread inflammation affecting the entire body, which can occur in severe cases of COVID-19 and contribute to complications like AKI. |
| Vasopressors | Medications that tighten blood vessels and raise blood pressure. Used in patients with very low blood pressure. |
| Hemoglobin | A protein in red blood cells that carries oxygen from the lungs to the rest of the body. Lower levels can indicate anemia or blood loss. |
| Lactate Dehydrogenase (LDH) | An enzyme that helps produce energy in cells. High levels in the blood can indicate tissue damage or disease. |
| Ferritin | A protein that stores iron in the body. High levels can indicate inflammation or infection. |
| Troponin | A protein released into the blood when the heart muscle is damaged. High levels can indicate a heart problem. |
| Blood Urea Nitrogen (BUN) | A waste product in the blood that comes from the breakdown of protein. High levels can indicate kidney problems. |
| Urine Dipstick Test | A simple test used to check for the presence of certain substances in the urine, such as protein or blood, which can indicate kidney problems. |
| Echocardiography (ECHO) | An ultrasound test that uses sound waves to create images of the heart, used to check heart function. |
| Chest X-ray and Computed Tomography (CT) | Imaging tests used to get detailed pictures of the chest and other parts of the body to check for issues like lung infections. |
| Systemic Pro-inflammatory Response | The body’s widespread inflammatory reaction to infection, which can cause symptoms and complications like AKI. |
| Vascular Permeability | When blood vessels allow more fluid to pass through their walls, which can lead to swelling and other issues. |
| Hospital Length of Stay | The duration of time a patient spends in the hospital. |
| Pediatric Intensive Care Unit (PICU) | A special hospital unit for children who are very sick and need intensive medical care. |
| Anticoagulant Therapy | Treatment with medications that prevent blood clots, which can help reduce complications in severe COVID-19 cases. |
Discussion
There have been relatively few studies focusing on AKI in children [8, 11]. Although a high incidence of AKI has been reported as a prominent feature in adult COVID-19 infection [2, 12, 13], a lower incidence of AKI in children has been shown [8, 11, 14]. One of the studies reporting a lower rate of AKI was a retrospective study conducted on 238 pediatric hospitalized patients and outpatients in China, in whom AKI was present in only 3 patients (1.2%) [14], much lower than that reported in the United States (24%) [11], and in the United Kingdom (29%) [15]. A meta-analysis reported that 44% of critically ill children (a total of 106) developed AKI according to the KDIGO serum creatinine criteria [16]. The discrepancies in the frequency of COVID-19-associated AKI among countries may be explained by different inclusion criteria (age, severity of illness, hospitalized or outpatients, intensive care admissions, and different definitions of AKI), regional differences, and different demographic characteristics of the study populations [17].
Although conflicting results have been reported, comorbidities generally increase the severity of AKI in patients with COVID-19. The presence of comorbidities, such as respiratory diseases, cardiac diseases, hematological disorders, and malignancies are likewise important in children with COVID-19 who developed AKI [6, 19,20,21]. A systematic review reported the rate of underlying comorbid disease in children with AKI as 26.7% [21]. Our patients showed a similar prevalence of comorbidities (28.6%) and 52.5% of patients with AKI had underlying diseases. A higher prevalence of comorbidities has been reported in adult patients with COVID-19-associated AKI [18]. By comparison with adults, pediatric patients had a lower prevalence of, and different comorbidities. COVID-19 and AKI may lead to worsening of comorbid disease [1]. However, we observed similar comorbidities in COVID-19 patients with and without AKI (p > 0.05). Providing early treatment may be an explanation for our positive results. A child with a comorbid disease is usually overprotected by parents and may have been brought to medical attention earlier than others, which might have reduced kidney injury by allowing timely medical interventions.
Various mechanisms are possibly involved in kidney injury during COVID-19 infection, including direct infection of the kidney parenchyma by the virus, endothelial injury, ischemic acute tubular necrosis, Renin–Angiotensin–Aldosterone System imbalance, microthrombosis, increased vascular permeability, and volume depletion, as well as the development of kidney damage secondary to hemodynamic instability, inflammatory cytokines, and therapeutic approaches (nephrotoxic medications, mechanical ventilation) [3, 6, 11, 22]. Studies have shown that the etiologies of AKI in patients with COVID-19 seem to be multifactorial, which is also consistent with our results. A meta-analysis reported that fever and gastrointestinal symptoms were more common in children with AKI associated with COVID-19 [3, 6, 11]. The present study showed that the main risk factors for the development of AKI were older age and the presence of abdominal pain, dyspnea, fever, nasal congestion, or anorexia as initial symptoms. All of these symptoms may lead to decreased fluid intake and increased fluid loss, which are triggering factors for the development of AKI in patients. Young children, and especially infants, with COVID-19 are more prone to develop gastrointestinal symptoms of COVID-19, and dehydration significantly increases the risk of AKI [14]. Hemodynamic monitoring with appropriate fluid management and vasopressor drugs are required to provide adequate renal perfusion in AKI patients. In our study, the need for vasopressors was higher in AKI patients (p < 0.001). We observed that AKI was associated with abdominal pain, but not nausea, vomiting, and diarrhea in our patients. These unexpected results can be explained by the fact that the amount of vomiting and diarrhea in our patients was not high enough to cause fluid loss. Due to the retrospective nature of our study, the frequency and amount of both vomiting and diarrhea are unknown.
It has been suggested that the systemic pro-inflammatory response may play an important role in the development of AKI in COVID-19 patients [6, 11, 17, 22]. Similarly, in our study, increased WBC and neutrophil count, increased NLR, increased serum levels of CRP and ferritin, and decreased serum albumin levels were found to be statistically significant for AKI patients compared to patients without AKI. The lower serum albumin and consequently lower serum calcium levels we detected in our patients with AKI may be explained by increased capillary permeability secondary to systemic inflammation.
Proteinuria was detected in 10.5% of our AKI patients by urinalysis and AKI was significantly associated with the presence of proteinuria (p = 0.022). Although it is known that febrile episodes can cause transient proteinuria in children, we could not show any difference in proteinuria between the patients with or without fever (p = 0.261). On the other hand, unlike other infections that cause transient proteinuria [10], COVID-19 may act directly on the kidney through multiple mechanisms [3, 22].
The present study confirmed that AKI was a risk factor for admission to hospital and the pediatric ICU, and that patients with AKI were more likely to require longer hospital stays. The association between AKI and admission to the ICU, and hospital length of stay has also been reported by other pediatric studies [6, 11, 19]. This association may be explained by hemodynamic instability and a diagnosis of AKI. In the present study, we did not find a statistically significant relationship between AKI stage and hospitalization requirement, admission to the ICU and length of hospital stay. It may be speculated that the medical care or attention given to patients with COVID-19 could positively influence the outcomes of patients who receive an early diagnosis of AKI. It may also reflect the early management of transient renal ischemia, which can cause an increase in serum creatinine. This may also be explained by our small sample size.
Mechanical ventilation and nephrotoxic medications were reported as risk factors for AKI development in children with COVID-19 in a retrospective chart review of children [6, 11, 19].
In the present study, most AKI patients were critically ill and required mechanical ventilation and multiple medications. These results were also consistent with already reported AKI findings in seriously ill children [23]. In this study, there was no significant difference between AKI and use of medications, except for vasopressor drugs. Nephrotoxic medications (i.e., nonsteroidal anti-inflammatory drugs, aminoglycosides, trimethoprim/sulfamethoxazole, vancomycin, and acyclovir) are commonly used in most cases. Early identification of AKI and supportive therapy may have helped in the rapid recovery of patients with COVID-19 and AKI, and may also have the potential to decrease the use of nephrotoxic medications. Efficient anti-inflammatory therapy makes prompt renal recovery possible. A beneficial effect of anticoagulant therapy on reducing COVID-19 mortality has been reported [24].
Acute kidney injury has a significant effect on mortality in COVID-19 patients, and higher AKI stage is associated with greater mortality. COVID-19 patients with AKI had a significantly higher risk of mortality compared to COVID-19 patients without AKI [11, 19, 24]. We found a mortality rate of 1.4% in COVID-19-positive patients. This was lower than the AKI mortality rate of 3.3% reported in the literature regarding patients with COVID-19 [25].
Our study has several limitations. Firstly, a baseline serum creatinine measurement was unavailable as most of our COVID-19 patients were previously healthy. Also, given the observational nature of this study, information on serum creatinine levels could not be retrieved as it was not usually evaluated in outpatients. Therefore, we cannot generalize our findings for AKI outpatients. The baseline serum creatinine level was unknown for some patients, which may have caused under-reporting of AKI diagnoses. The second limitation of our study is that only PCR-positive confirmed COVID-19 patients were included, and the sensitivity reported in clinical practice ranges from 42 to 83%, depending on the patient’s symptom duration and viral load, and the quality of the test sample. Thirdly, we may have missed asymptomatic or mildly symptomatic patients treated at home. The lack of examination on tubular proteinuria is a further limitation of this study. Despite these limitations, this study draws its strength from the inclusion of AKI patients in both outpatient and inpatient settings [26].
In conclusion, AKI was diagnosed in 3.7% of outpatients and in 23.9% of hospitalized pediatric patients with COVID-19. Our findings highlight that children with higher levels of inflammation markers, particularly a higher NLR and lower serum albumin levels on admission, may be more prone to develop COVID-19-associated AKI. In the present study, COVID-19 patients complicated by AKI had more co-morbidities, lower hemoglobin levels, and higher serum glucose and lactate dehydrogenase levels on admission. We also showed that pediatric COVID-19 patients with AKI requiring hospitalization had more admissions to the PICU, longer hospital stays, and greater need for mechanical ventilation compared to those without AKI. Patients with COVID-19 AKI had a higher risk of mortality than patients with COVID-19 without AKI. Given the link between COVID-19-associated AKI and both mortality and poor prognosis, the outcome of this study suggests that renal function in children should be closely monitored.
reference : https://link.springer.com/article/10.1007/s40620-024-01986-9
