Part 1: Acute Kidney Injury in Pediatric Patients Hospitalized With Acute COVID-19 And Multisystem Inflammatory Syndrome in Children Associated With COVID-19

Part 1: Acute kidney injury in pediatric patients hospitalized with acute COVID-19 and multisystem inflammatory syndrome in children associated with COVID-19

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Keywords: acute kidney injury, COVID-19, pediatric nephrology, kidney

Background

This study describes the incidence, associated clinical characteristics, and outcomes of acute kidney injury in a pediatric cohort with COVID-19 and Multisystem Inflammatory Syndrome in Children (MIS-C). We performed a retrospective study of patients 18 years of age and under admitted to four New York hospitals in the Northwell Health System interned during the height of the COVID-19 pandemic, between March 9 and August 13, 2020. Acute kidney injury was defined and staged according to Kidney Disease: Improving Global Outcomes criteria. The cohort included 152 patients; 97 acute-COVID-19 and 55 with MIS-C associated with COVID-19. Acute kidney injury occurred in 8 with acute-COVID-19 and in 10 with MIS-C. Acute kidney injury, in unadjusted models, was associated with a lower serum albumin level (odds ratio 0.17; 95% confidence interval 0.07, 0.39) and higher white blood cell counts (odds ratio 1.11; 95% confidence interval 1.04, 1.2). Patients with MIS-C and acute kidney injury had significantly greater rates of systolic dysfunction, compared to those without (80% vs 49%). In unadjusted models, patients with acute kidney injury had 8.4 days longer hospitalizations compared to patients without acute kidney injury (95% confidence interval, 4.4-6.7). Acute kidney injury in acute-COVID-19 and MIS-C may be related to inflammation and/or dehydration. Further research in larger pediatric cohorts is needed to better characterize risk factors for acute kidney injury in acute-COVID-19 and with MIS-C consequent to COVID-19.

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By October 2020, the United States had >7.5 million cases of coronavirus disease 2019 (COVID-19). 1–4 Initially considered a respiratory illness, COVID-19 has proven to be a complex multisystem illness frequently associated with kidney injury.

Acute kidney injury is a common complication in adults with COVID-19. Initial studies from China and Italy reported acute kidney injury rates as high as 29%. 6,9–15 A recent study from our health system reported a significantly higher incidence of acute kidney injury in adult patients (36.6%) and found acute kidney injury to be associated with morbidity and mortality. 5,16 These incidences and mortality risks were corroborated in subsequent US studies.

Although several studies are describing COVID-19–related acute kidney injury in adults, limited data are describing acute kidney injury in pediatric patients with acute COVID-19. A retrospective observational study of 238 pediatric patients admitted to Wuhan Children’s Hospital with COVID-19 reported a 1.2% incidence of acute kidney injury. 17 Recent studies from the United Kingdom and Saudi Arabia reported an incidence rate of pediatric acute kidney injury between 21% and 29%. 18,19 A preliminary report from a multicenter study evaluating acute kidney injury in 106 critically ill children with acute COVID-19, including 32 US sites, reported a point prevalence rate of 44% (N ¼ 47).

Children initially thought to be spared from serious effects of COVID-19, are vulnerable to sequelae. In May of 2020, the Centers for Disease Control and Prevention released a public health advisory along with a case definition for multisystem inflammatory syndrome in children (MIS-C) associated with recent COVID-19 infection. 21 These children presented with features similar to typical Kawasaki disease or toxic shock syndrome. 22 Recent reports of children with MIS-C have highlighted the incidence of acute kidney injury in this subset. 22,23 In a systematic review of 662 patients with MIS-C, 108 (16.3%) developed acute kidney injury; however, the definition of acute kidney injury differed between centers.

Although there is early data that acute kidney injury develops in pediatric patients with acute COVID-19 and MIS-C, the rates, associated clinical characteristics, and short-term outcomes are not well characterized. Therefore, we aimed to describe the incidence of acute kidney injury in these populations, assess associated demographic and clinical factors in those who had acute kidney injury, and determine the association of acute kidney injury with a length of time on mechanical ventilation, length of stay, and mortality.

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METHODS

Study design

A retrospective chart review of children admitted to the Northwell Health system with acute COVID-19 and MIS-C was conducted. Participating hospitals were within the New York metropolitan area and included Cohen Children’s Medical Center, an academic tertiary children’s hospital, as well as 3 tertiary hospitals: South Shore Hospital, Staten Island University Hospital, and Lenox Hill Hospital. Data from March 9, 2020, through August 13, 2020, were collected retrospectively using the inpatient electronic health record Sunrise Clinical Manager (Allscripts, Chicago, Illinois). This study was approved by the Institutional Review Board of Northwell Health.

Our study included children aged #18 years who were admitted for treatment of acute COVID-19 or MIS-C. Patients were considered to have acute COVID-19 if, within 24 hours of admission, they tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by polymerase chain reaction testing (Northwell Health Labs). The Centers for Disease Control and Prevention case definition of MIS-C was utilized: children who presented with fevers, significant evidence of inflammation, evidence of $2 organ dysfunction, and tested positive for current or recent SARS-CoV-2 infection or had serologic confirmation of exposure to COVID-19 within 4 weeks of symptom onset. 20 Patients who were pregnant, kidney transplant recipients, patients with end-stage kidney disease (estimated glomerular filtration rate <15 ml/min per 1.73 m 2 or dialysis), or those transferred from outside of the health system were excluded.

Incidence of acute kidney injury

The primary outcome of this study was the incidence rate of acute kidney injury. The diagnosis and staging of acute kidney injury were conducted by the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines. 24 Only serum creatinine was used to define and stage acute kidney injury as the documentation of urine output in the electronic health record was not reliably documented. None of the patients had baseline serum creatinine available (defined as creatinine within 3 months of admission); therefore, as previously described in the literature, baseline creatinine was estimated by back-calculating from the original Schwartz formula assuming a normal glomerular filtration rate for children (estimated glomerular filtration rate set as 120 ml/min per 1.73 m 2 ). 25 If height was not documented, the average height (Centers for Disease Control and Prevention 50th percentile) was imputed for sex and age (N ¼ 8).

Associations with acute kidney injury

Secondary outcomes included demographic and clinical factors associated with the development of acute kidney injury. The following measures were evaluated: patient demographics, presenting symptoms, and comorbid conditions. Laboratory measurements included serum electrolytes, creatinine, blood urea nitrogen, albumin, d-dimer, inflammatory markers, and hematologic markers. Details regarding hospital stay, such as the usage of vasoactive medications, i.v. Ig, corticosteroids, extracorporeal membrane oxygenation (ECMO), and exposure to nephrotoxic medications, were also collected. In patients with MIS-C, 2-dimensional echocardiographic data were included. Nadir left ventricular systolic ejection fractions were utilized to define the lowest left ventricular ejection fraction during hospitalization. Systolic dysfunction was defined as left ventricular ejection fraction <55%. Coronary artery dilation was defined as >2 mm.

Clinical course and outcomes

The impact of acute kidney injury (all stages combined and severe, stages 2 and 3) on clinical course and outcomes was also evaluated. Outcomes included mortality, kidney replacement therapy, length of mechanical ventilation, length of hospital stay, and pediatric intensive care unit (PICU) stay.

Statistical analysis

Baseline demographic and clinical characteristics were described according to admission type, acute COVID-19, and MIS-C, respectively. Continuous data were described utilizing medians and interquartile ranges (IQRs), and categorical data were presented as frequencies and proportions. Mann-Whitney U test, c 2 test, Kruskal-Wallis test, and Fisher exact test were utilized to compare baseline characteristics of acute COVID-19 and MIS-C patients with and without acute kidney injury.

Logistic regression analysis was performed to identify factors associated with acute kidney injury (both MIS-C and acute COVID-19 combined). Because of the low acute kidney injury frequency, we were not powered to adjust for confounders in our models. Multiple imputations were used for missing values in regression analysis. Subsequently, simple linear regression analysis was performed to assess the relationship between acute kidney injury and continuous outcomes, including PICU and hospital length of stay and length of time on mechanical ventilation. Two-tailed P < 0.05 was set as the level of significance, and SPSS version 26 was used for analysis.

RESULTS

Of the 166 children admitted for acute COVID-19 or MIS-C, 152 met inclusion criteria. Over 63% (N ¼ 97) patients were admitted for acute COVID-19, whereas 55 patients (36.2%) were diagnosed with MIS-C (Figure 1). Acute kidney injury developed in 18 (11.8%) of all patients. Demographic data, presenting symptoms, and baseline laboratory values of those with and without acute kidney injury in both groups were compared (Tables 1 and 2).

Acute COVID-19

The median age of children with acute COVID-19 was 8.2 (IQR, 1.5–13.8) years, and more than half were male. Eight patients (8.2%) developed acute kidney injury; 4 presented with acute kidney injury on admission (Table 1, 25, and Figure 2); 6 (6.2%) had stage 1, and 2 had stage 3 (Supplementary Table S1). There were no significant differences in age, sex, race, and body mass index z-score among children with and without acute kidney injury. Although there was no significant difference in presenting symptoms, 50% of patients with acute kidney injury presented with gastrointestinal symptoms. Patients with acute kidney injury presented with significantly lower serum calcium and albumin (P ¼ 0.047 and P ¼ 0.001, respectively). Baseline white blood cell (WBC) count was significantly higher in those with acute kidney injury compared with those without acute kidney injury (P ¼ 0.02) (Table 1).

Multisystem inflammatory syndrome in children

The median age of children hospitalized with MIS-C was 7.5 (IQR, 1.5–13.8) years, and >60% were male. acute kidney injury developed in 10 (18.2%) patients. Eight (80%) of these patients presented with acute kidney injury on admission; 4 (7.3%) had stage 1, 2 (3.6%) had stage 2, and 4 (7.3%) had stage 3 (Figure 2 and Supplementary Table S1). There were no significant differences in age, sex, race, or ethnicity between the 2 groups. Those with acute kidney injury had a greater median body mass index z-score compared with those who did not develop acute kidney injury (P ¼0.045). All patients in the MIS-C group were hospitalized in a children’s hospital. Although there was no significant difference in presenting symptoms, all MIS-C patients with acute kidney injury presented with gastrointestinal symptoms. Patients with acute kidney injury had lower serum bicarbonate and albumin at presentation (P ¼ 0.02 and P ¼ 0.004, respectively). Baseline C-reactive protein was also significantly elevated among MIS-C patients who developed acute kidney injury (P < 0.0001). Although not statistically significant, patients with acute kidney injury presented with a higher WBC count (Table 2,25 ).

Echocardiography was available and analyzed for 89% of MIS-C patients (N ¼ 49). Median left ventricular ejection fraction was lower for those with acute kidney injury (49%; IQR, 40%–54%) compared with those without acute kidney injury (56%; IQR, 49%–62%) (P ¼ 0.02). Systolic dysfunction occurred in 80% (N ¼ 8) of acute kidney injury patients compared with 49% (N ¼ 17) without acute kidney injury. Coronary artery dilation (>2 mm) did not differ significantly between the groups (Supplementary Table S2).

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