Scientific Papers

A retrospective analysis of acute kidney injury in children with post-COVID-19 multisystem inflammatory syndrome: insights into promising outcomes | Italian Journal of Pediatrics

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At the beginning of the pandemic, children were considered to be at lower risk of COVID-19, with a lower incidence of infection and milder clinical course [15]. Later, small cohort studies and case reports highlighted kidney involvement in children with COVID-19 infection [16, 17]. There have also been few reports supporting a high risk of AKI occurrence in MIS-C, related COVID-19 infection [9] however, there has been no consensus regarding the accurate incidence, outcomes, and related mortality among this population. Therefore, our study was executed to address the prevalence of AKI in children with post-COVID MIS-C and to assess severity and outcome in different stages.

The reported incidence of AKI in children with COVID-19 infection is highly variable between studies. In the current study, 51 patients were diagnosed with AKI, which represented 37% of patients with MIS-C-related COVID-19 and 7.8% of total COVID-19 patients admitted to our hospital during the study period. Grewal et al., reported AKI in 24% of total COVID cases, with a differential incidence of 54% among MIS-C patients and only 9% in those with acute SARS-CoV-2 infection without MIS-C [12], and in a recent systematic review, AKI was reported in 20% of MIS-C patients [9]. This variability could be related to variances in AKI definitions applied, rates of hospitalization, concomitant comorbid factors, and incidence of MIS-C cases. A systematic review reported that the incidence of AKI was also higher in studies that used the KDIGO definition of AKI (24%) than in studies that used alternative definitions of AKI (18%), and there was a slightly higher proportion of children developing AKI in single-center studies (23%) than in multicenter studies (20%) [9]. The incidence of AKI in pediatric patients is variable, ranging from 5–37% in the PICU with variable requirements for KRT; therefore, patients with MIS-C have a comparable risk of AKI when compared to patients in the PICU due to other causes [18, 19].

The mechanism of AKI in SARS-CoV-2 patients is multifactorial, including dehydration, poor cardiac output, cytokine storm and microvascular thrombosis [20] as well as the direct cytopathic effect of the virus on renal tubular cells due to the presence of angiotensin-converting enzyme 2 receptors, which serve as an entrance door for SARS-CoV-2, and the use of nephrotoxic drugs. However, the mechanism implicated in AKI development in MIS-C patients is chiefly due to renal hypoperfusion because those patients had longer durations of ICU stay, were more susceptible to hypoxemia, particularly if they developed ARDS [21], or needed more inotropic support and had higher markers of cardiac dysfunction compared to acute SARS-CoV-2-AKI patients [22, 23].

Fever and dyspnea were the most common presenting features in our patients (36/42, 85.7%, each). In addition, more than 30% of patients with stage 3 AKI needed oxygen therapy, and 50% needed invasive mechanical ventilation, which may support the role of hypoxemia in AKI pathogenesis. This is consistent with the findings of Sabaghian and colleagues, who reported a statistically significant increase in the number of cases with respiratory system involvement in adults with stage 3 AKI [24].

Different comorbidities have been reported to be associated with the development and worsening of AKI in MIS and COVID-19 infection in both adults and children. Grewal et al. reported that nearly 60% of children in the AKI group had underlying comorbidities: pulmonary (18%), neurological (8%), malignancies (7%), sickle cell disease (5%), hypertension (3%), immunosuppression (2%), type 1 (2%), type 2 diabetes mellitus (2%), and cardiac conditions (1%) [12]. Adult studies reported that the most common comorbidities were diabetes, hypertension and hyperlipidemia that were documented in 40%, 61.4% and 57.1% of patients with COVID-19 and AKI, respectively [25], while a history of previously diagnosed CKD was reported in 22.2% of patients [23].

Kidney biopsy was performed in 3 cases in our cohort. Recognizing and properly diagnosing renal involvement in patients with COVID-19 could be challenging (due to the lack of direct proof of viral infection, e.g., viral particles) and requires a proper integration of clinical and pathological data [26]. A wide range of renal pathological findings have been described to associate COVID-19 infection in adults both in native and transplanted kidneys, such as collapsing glomerulopathy (CG) and other forms of focal segmental glomerulosclerosis, acute tubular necrosis (ATN), IgA nephropathy, thrombotic microangiopathy, crescentic glomerulonephritis, minimal change disease, membranous nephropathy, and anti-glomerular basement membrane disease [27,28,29,30,31,32,33]. SARS-CoV-2 antigens have been detected by immunohistochemistry in kidney tubules, and virus particles were detected in the renal tubular epithelium and podocytes by transmission electronic microscopy [34]. COVID-19-related immune thrombosis is due to macrophage activation and cytokine storms leading to elevated CRP, ferritin and D-dimer levels, which are correlated with worse outcomes [35]. Scarce renal pathological reports in children with COVID-19 infections are available including minimal change disease, C3 glomerulopathy [26], acute necrotizing glomerulonephritis [36], diffuse and segmental mesangial-proliferative glomerulonephritis and acute tubule-interstitial nephritis [37].

Stage 3 AKI patients reported significantly higher WBCs count, ESR, serum ferritin and creatinine on admission, while no significant difference was detected between AKI stages regarding age, associated comorbid diseases, need for inotropes and mechanical ventilation. Tastemel Ozturk et al. reported a significant relationship between older age and AKI in MIS-C patients in univariate analysis, which was lost in multivariate analysis [38]. The median age of patients with AKI was more likely to be younger than that of patients without AKI (9 years vs. 10.5 years; p = 0.08) [39]. Higher values of inflammatory biomarkers, such as WBCs, CRP, procalcitonin, D-dimer, ferritin and IL-6, were observed in MIS-C patients presenting with AKI. In the same studies associated with systolic dysfunction, the need for inotropes and lower levels of albumin and bicarbonates were monitored. Therefore, these data suggest a double component in the pathogenesis of AKI in MIS-C due to both an inflammatory pathway and prerenal injury [40,41,42].

Hemodialysis (conventional and hemodiafiltration) was initiated in 5 patients (AKI stage 3), and 5–12 sessions were performed per patient. Unfortunately, continuous renal replacement therapy (CRRT) was not available at our institution at that time, so intermittent dialysis was used. KRT in the setting of multiorgan disease syndrome should be initiated with expertise. KRT can be utilized non-selectively to clear inflammatory mediators via convection, adsorption and diffusion. CRRT corrects fluid overload and manages solute levels to provide hemodynamic stability in catabolic pediatric patients [43]. Immediate initiation of preemptive KRT in cases with progressive symptomatic respiratory insufficiency improves overall outcomes. The pediatric CRRT group advises the early initiation of KRT in critically ill COVID-19-related immune dysregulation syndrome patients as it has been shown to mitigate fluid overload, enhance cytokine clearance, improve oxygenation and create hemodynamic stability earlier, leading to better overall outcomes, but if CRRT is not available, intermittent hemodialysis is satisfactory [44].

The mean duration of PICU stay for patients with AKI with previously normal kidney function was 9.9 days, with the longest duration reported in AKI stage 3 (20 days). Grewal et al. reported that all patients in the MISC-AKI group needed admission to the PICU with a median duration of PICU stay in patients with AKI of 7.5 days [12], while Özen et al. (2023) reported a length of stay in the PICU of 8 days [45]. These differences may be related to differences in the severity of cases and standards for PICU admission and discharge.

Only 2 mortalities were reported in our cohort, representing 4.8% of 42 cases with AKI, 1.4% of 138 MISC-related COVID-19 cases and 0.3% of total COVID-19 cases admitted over 2 years. A report from North America reported a 7.7% mortality rate among 274 pediatric COVID patients with AKI [46], while a report from Saudi Arabia stated that AKI was significantly associated with mortality (42% vs. 0%), compared to patients with normal kidney function, and after adjustment for age, sex, and the presence of comorbidities, AKI was still drastically associated with mortality [7]. Bjornstad et al., a multicenter study throughout the United States, Eastern Europe, and Russia, reported a mortality rate of 6% among AKI COVID-19 pediatric patients and 5% among pediatric COVID-19 patients without AKI [16].

AKI is considered an independent risk factor for increased mortality in critically ill patients with any disease [47]. Kidney involvement has also been reported as an indicator of poor prognosis irrespective of initial COVID-19 severity [48], yielding avoidance of nephrotoxic drugs, early detection and prompt management of renal function abnormalities improve the prognosis, which can explain the low mortality rates in our cohort. Additionally, no residual renal impairment was reported in 29 children (with previously normal kidney function) at the time of discharge, and all had normal urine analysis and serum creatinine during the 6-month follow-up period. This is inconsistent with the findings of Kari et al., who reported that 9% of their study population had residual renal impairment at the time of discharge and that factors associated with residual renal impairment were decreased tissue perfusion, sepsis, worsening clinical condition, or comorbidities [7]. Tastemel Ozturk et al. reported AKI recovery at discharge to be 63.6% in COVID-19 survivors and 100% in MIS-C patients [38].

Strengths and limitations

This is the first study to present the epidemiological features and outcomes of AKI in Egyptian children with MIS-C-related COVID-19 infection. The limitations of the study include the limited number of subjects (owing to the percentage of MISC among COVID children), being a single center study, the retrospective nature of the study, the changes in virus virulence and emergence of new variants in this process due to the long period in which the patients were included, and the changes in the treatments applied and not including a non-AKI group for comparison.

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