COVID-19 and the multisystem inflammatory syndrome in children: how vulnerable are the kidneys?
Authors: Vimal Chadha, Bradley A. Warady
Journal: Kidney International (2021)

When affected by coronavirus disease 2019 (COVID-19), most children have milder disease than what is experienced by adults. However, a subset of these children develops a multisystem inflammatory syndrome that can lead to shock and multiorgan failure. In the current issue, Basalely et al. characterize acute kidney injury in pediatric patients with acute COVID-19 and multisystem inflammatory syndrome. Despite the associated morbidity, this cohort provides evidence of kidney recovery in most affected children. When affected by coronavirus disease 2019 (COVID-19), most children have milder disease than what is experienced by adults. However, a subset of these children develops a multisystem inflammatory syndrome that can lead to shock and multiorgan failure. In the current issue, Basalely et al. characterize acute kidney injury in pediatric patients with acute COVID-19 and multisystem inflammatory syndrome. Despite the associated morbidity, this cohort provides evidence of kidney recovery in most affected children. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged as the cause of coronavirus disease 2019 (COVID-19) in Hubei province, China, in December 2019 and was declared a pandemic in March 2020. Although the adult case fatality rate of 3.4% for SARS-CoV-2 is lower than those reported for SARS-CoV-1 in 2003 (9.6%) and Middle East respiratory syndrome coronavirus (35%), the former is much more contagious and as a result has become a pandemic of historic proportions. COVID-19 and its 2 predecessors share many important features in their clinical presentations and in their propensity for progression to severe disease involving multiple organs with high rates of morbidity. Although predominantly a respiratory infection, COVID-19 often progresses to a multisystem disorder, with kidney involvement common in adult patients who experience moderate to severe disease. Early reports from China described high rates of hematuria and proteinuria, but relatively low rates of acute kidney injury (AKI), associated with COVID-19. Highly variable rates of AKI in adults have since been reported from Europe and the United States, with a lack of uniformity in the cohort being described (e.g., hospitalized vs. intensive care) believed to be an important factor resulting in the variability of reported rates, and a factor further impacted by the evolution of hospitalization patterns that has occurred over the course of the pandemic. For example, although AKI occurred in 56.9% of 3345 hospitalized adults with COVID-19 in the Montefiore Health System (Bronx, NY), a much higher rate (87.2%) was seen in the subset of patients who required intensive care unit (ICU) admission.1Fisher M. Neugarten J. Bellin E. et al.AKI in hospitalized patients with and without COVID-19: a comparison study.J Am Soc Nephrol. 2020; 31: 2145-2157Crossref PubMed Scopus (248) Google Scholar This rate of ICU-related AKI is greater than the rate of 57.3% reported by the Acute Kidney Injury–Epidemiologic Prospective Investigation study (international cross-sectional study performed in 97 ICUs) that found similar risk-adjusted rates of AKI and mortality worldwide.2Hoste E.A.J. Bagshaw S.M. Bellomo R. et al.Epidemiology of acute kidney injury in critically ill patients: the multinational AKI-EPI study.Intensive Care Med. 2015; 41: 1411-1423Crossref PubMed Scopus (1778) Google Scholar Studies comparing the risk of AKI in COVID-19 patients with retrospective cohorts of patients hospitalized with severe influenza have found that although the overall risk of AKI was similar in the 2 groups of patients, stage 3 AKI, as defined by Kidney Disease: Improving Global Outcomes (KDIGO), was almost 3 times more common in patients with COVID-19.3Bhasin B. Veitla V. Dawson A.Z. et al.Acute kidney injury in hospitalized patients with COVID-19 and seasonal influenza: a comparative analysis.Kidney 360. 2021; 2: 619-628Crossref PubMed Scopus (6) Google Scholar A substantial percentage (up to 28.5%) of adult COVID-19 patients with AKI have, in turn, been reported to require renal replacement therapy, a development that has been associated with mortality rates as high as 75% to 90%.1Fisher M. Neugarten J. Bellin E. et al.AKI in hospitalized patients with and without COVID-19: a comparison study.J Am Soc Nephrol. 2020; 31: 2145-2157Crossref PubMed Scopus (248) Google Scholar,2Hoste E.A.J. Bagshaw S.M. Bellomo R. et al.Epidemiology of acute kidney injury in critically ill patients: the multinational AKI-EPI study.Intensive Care Med. 2015; 41: 1411-1423Crossref PubMed Scopus (1778) Google Scholar,4Ng J.H. Hirsch J.S. Hazzan A. et al.Outcomes among patients hospitalized with COVID-19 and acute kidney injury.Am J Kidney Dis. 2021; 77: 204-215.e1Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar In addition, up to one-third of those who have survived following renal replacement therapy did not achieve full recovery of kidney function at the time of discharge.4Ng J.H. Hirsch J.S. Hazzan A. et al.Outcomes among patients hospitalized with COVID-19 and acute kidney injury.Am J Kidney Dis. 2021; 77: 204-215.e1Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar For reasons that are still speculative, children and adolescents make up a small proportion of COVID-19 cases. National statistics from countries in Asia, Europe, and North America have revealed that pediatric cases account for 2.1% to 7.8% of confirmed COVID-19 cases; however, the actual incidence is likely much higher as COVID-19 disease in most children and adolescents is associated with mild symptoms (if any symptoms at all) and may not prompt confirmatory testing. The mild symptoms of the disease in children, with particular reference to kidney function, were initially borne out in a retrospective observational study of 238 children admitted to Wuhan Children's Hospital with COVID-19, in which the reported incidence of AKI was only 1.2%. Subsequent pediatric studies from Saudi Arabia and the United Kingdom did report much higher AKI rates of between 21% and 29% in children hospitalized with COVID-19, highlighting the importance of further investigation of this complication in children. In this issue of Kidney International, Basalely et al. do just that by providing additional data on the incidence, clinical characteristics, and outcomes of COVID-19 in a cohort of 152 children (aged <18 years) who were admitted to 4 New York hospitals during the height of the COVID-19 pandemic.5Basalely A. Gurusinghe S. Schneider J. et al.Acute kidney injury in pediatric patients hospitalized with acute COVID-19 and multisystem inflammatory syndrome in children associated with COVID-19.Kidney Int. 2021; 100: 138-145Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar AKI developed in 11.8% (18 patients) of this cohort (combined acute COVID-19 and multisystem inflammatory syndrome in children [MIS-C]) and completely resolved in 83% of them. These findings are in contrast to a cross-sectional point prevalence study of AKI in COVID-19 patients that reported the development of AKI in nearly half (44%) of 106 children admitted to ICUs in 41 centers, 32 of which were United States based.6Bjornstad E.C. Krallman K.A. Askenazi D. et al.Preliminary assessment of acute kidney injury in critically ill children associated with SARS-CoV-2 infection: a multicenter cross-sectional analysis.Clin J Am Soc Nephrol. 2021; 16: 446-448Crossref PubMed Scopus (29) Google Scholar It is noteworthy that the AKI rate in the cohort reported by Basalely et al. increases to 28% if only the 60 patients who required intensive care are considered. Of interest, this AKI rate is similar to the rate of 26.9% seen in a review of 4683 patients reported by the Assessment of Worldwide Acute Kidney Injury, Renal Angina, and Epidemiology (AWARE) study, a multinational, prospective study designed to describe AKI epidemiology in critically ill children.7Kaddourah A. Basu R.K. Bagshaw S.M. Goldstein S.L. Epidemiology of acute kidney injury in critically ill children and young adults.N Engl J Med. 2016; 376: 11-20Crossref PubMed Scopus (689) Google Scholar In addition, the percentage of ICU patients with severe AKI (KDIGO AKI stage 2–3) reported by Basalely et al. (13.3%) also approximates the incidence of severe AKI (11.6%) seen in the AWARE study. The length of hospitalization was significantly impacted by the presence of AKI, and one patient with AKI (representing 5% of all AKI patients and 12.5% of those with severe AKI) died, with the latter rate being similar to that reported by AWARE (11% mortality with severe AKI), but significantly less than the adult COVID-19 experience. Unique to the pediatric population of COVID-19 patients has been the development of a constellation of clinical findings coined the MIS-C. In mid-May 2020, the Centers for Disease Control and Prevention published a case definition for this syndrome, characterized by fever and inflammation (Table 1), a presentation similar to Kawasaki disease. It was detected in children and adolescents, aged <21 years, and was found to be temporally associated with SARS-CoV-2 infection. MIS-C is hypothesized to be primarily postinfectious in nature and distinct from COVID-19 as it occurs 2 to 4 weeks after infection with SARS-CoV-2. Although this COVID-19–associated disorder is uncommon (2 in 100,000 persons aged <21 years) when compared with COVID-19 cases (322 in 100,000), it can lead to serious and life-threatening complications. The disorder is distinct from Kawasaki disease as patients with MIS-C are older (average age, >7 years), have intense inflammation, and have greater myocardial injury than patients with Kawasaki disease, and are more likely to be non-Hispanic Blacks. Because of the multisystem involvement that is characteristic of MIS-C, there have been concerns regarding the possible frequent development of AKI in this group of patients as a higher percentage (80%) of them receive intensive care, 20% receive mechanical ventilation, and 48% receive vasoactive support, all of which are associated with a higher risk of AKI.8Ahmed M. Advani S. Moreira A. et al.Multisystem inflammatory syndrome in children: a systematic review.EClinicalMedicine. 2020; 26: 100527Abstract Full Text Full Text PDF PubMed Scopus (374) Google ScholarTable 1Centers for Disease Control and Prevention case definition for MIS-C•Aged <21 yr•Fever ≥38.0 °C for ≥24 h or report of subjective fever lasting ≥24 h•Laboratory evidence of inflammation, including but not limited to ≥1 of the following:○An elevated C-reactive protein, erythrocyte sedimentation rate, fibrinogen, procalcitonin, D-dimer, ferritin, lactate dehydrogenase, interleukin 6, elevated neutrophils, reduced lymphocytes, and hypoalbuminemia•Clinically severe illness requiring hospitalization with multisystem (≥2) organ involvement:○Cardiac, kidney, respiratory, hematologic, gastrointestinal, dermatologic, or neurologic•No alternative plausible diagnoses•Positive for current or recent SARS-CoV-2 infection by RT-PCR, antibody, or antigen test; or exposure to a suspected or confirmed COVID-19 case within the 4 weeks before the onset of symptomsCOVID-19, coronavirus disease 2019; MIS-C, multisystem inflammatory syndrome in children; RT-PCR, reverse transcription–polymerase chain reaction; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2. Open table in a new tab COVID-19, coronavirus disease 2019; MIS-C, multisystem inflammatory syndrome in children; RT-PCR, reverse transcription–polymerase chain reaction; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2. Fortunately, in a report of 186 patients with MIS-C from 26 states in the United States, AKI was diagnosed in <10%, while the most commonly involved organ systems were gastrointestinal (92%), cardiovascular (80%), hematologic (76%), mucocutaneous (74%), and respiratory (70%).9Feldstein L.R. Rose E.B. Horwitz S.M. et al.Multisystem inflammatory syndrome in U.S. children and adolescents.N Engl J Med. 2020; 383: 334-346Crossref PubMed Scopus (1774) Google Scholar In addition, in a recent report comparing the course of 577 children and adolescents with acute COVID-19 and 539 with MIS-C, the presence or absence of AKI was not even commented on. However, there has been a spectrum of AKI rates reported from pediatric centers globally, with most cases being mild and transient in nature (Table 2). In the publication by Basalely et al., 55 of the 152 hospitalized patients (36.2%) were, in fact, diagnosed with MIS-C. The greater severity of illness associated with MIS-C compared with acute COVID-19 disease in the remaining 97 patients was reflected by the greater percentage of children with MIS-C who developed AKI (18.2% vs. 8.2%), who had stage 3 AKI (40% vs. 25%), and who required intensive care (61.8% vs. 27%). Most of the patients (80% with MIS-C and 50% with COVID-19) who developed AKI were found to have decreased kidney function at the time of hospital admission, often with gastrointestinal symptoms, suggesting a possible prerenal etiology. Echocardiographic evidence of systolic dysfunction was more common in patients with MIS-C who had AKI compared with those who did not, a finding that has also been seen by others and that suggests the possible contribution of renal hypoperfusion to the impaired kidney function. Nevertheless, none of the patients with MIS-C required renal replacement therapy, and 9 of 10 patients had resolution of AKI before hospital discharge. With 6 of the 8 acute COVID-19 patients also demonstrating resolution of AKI, these data further suggest that the kidney injury in pediatric patients with COVID-19 and MIS-C is not severe in most instances.Table 2AKI rates in patients with SARS-CoV-2 disease (COVID-19 and MIS-C)First author, journalRegion, countrySingle center vs. multicenterSARS-Cov-2 disease categoryNo. of patientsAKI rate, %Qiu et al.S1Lancet Infect Dis.Zhejiang, ChinaMulticenterCOVID-19360Wang et al.S2Pediatr Nephrol.Wuhan, ChinaSingle centerCOVID-192381.3Kari et al.S3Res Sq.Kingdom of Saudi ArabiaMulticenterCOVID-198921Stewart et al.S4Lancet Child Adolesc Health.London,UKSingle centerCOVID-19 and MIS-C5229Bjornstad et al.6Bjornstad E.C. Krallman K.A. Askenazi D. et al.Preliminary assessment of acute kidney injury in critically ill children associated with SARS-CoV-2 infection: a multicenter cross-sectional analysis.Clin J Am Soc Nephrol. 2021; 16: 446-448Crossref PubMed Scopus (29) Google ScholarClin J Am Soc Nephrol.InternationalMulticenterDid not differentiate10644Basalely et al.5Basalely A. Gurusinghe S. Schneider J. et al.Acute kidney injury in pediatric patients hospitalized with acute COVID-19 and multisystem inflammatory syndrome in children associated with COVID-19.Kidney Int. 2021; 100: 138-145Abstract Full Text Full Text PDF PubMed Scopus (44) Google ScholarKidney Int.NY, USAMulticenterCOVID-19MIS-C9755818Whittaker et al.S5JAMA.UKMulticenterMIS-C5822Dufort et al.S6N Engl J Med.NY, USAMulticenterMIS-C9910Feldstein et al.9Feldstein L.R. Rose E.B. Horwitz S.M. et al.Multisystem inflammatory syndrome in U.S. children and adolescents.N Engl J Med. 2020; 383: 334-346Crossref PubMed Scopus (1774) Google ScholarN Engl J Med.USAMulticenterMIS-C1866Lipton et al.S7Kidney360.NY, USASingle centerMIS-C5746Grimaud et al.S8Ann Intensive Care.Paris, FranceMulticenterMIS-C2070Capone et al.S9J Pediatr.New York, USASingle centerMIS-C3370Lee et al.S10J Clin Invest.Boston,MA, USASingle centerMIS-C2821Miller et al.S11 Gastroenterology.NY, USASingle centerMIS-C4416Moraleda et al.S12Clin Infect Dis.SpainMulticenterMIS-C3113Pouletty et al.S13Ann Rheum Dis.Paris, FranceMulticenterMIS-C1656Toubiana et al.S14BMJ.Paris, FranceSingle centerMIS-C2152AKI, acute kidney injury; COVID-19, coronavirus disease 2019; MIS-C, multisystem inflammatory syndrome in children; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.Limited to reports with n > 10. Open table in a new tab AKI, acute kidney injury; COVID-19, coronavirus disease 2019; MIS-C, multisystem inflammatory syndrome in children; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2. Limited to reports with n > 10. At present, children aged <16 years are not eligible for vaccination against SARS-CoV-2 and thus we are likely to continue to see children with COVID-19 and MIS-C in the foreseeable future. Although the information presented by Basalely et al. is informative and optimistic in terms of the generally favorable AKI-related outcome, the limited experience presented precludes any definitive statement regarding the epidemiology of COVID-19–related AKI in children and highlights the importance of ongoing multicenter/national surveillance of the affected pediatric population with sharing of those experiences as a means to ideally optimize care until universal prevention can be achieved. All the authors declared no competing interests. Download .pdf (.01 MB) Help with pdf files Supplementary File (PDF) Acute kidney injury in pediatric patients hospitalized with acute COVID-19 and multisystem inflammatory syndrome in children associated with COVID-19Kidney InternationalVol. 100Issue 1PreviewThis 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. Full-Text PDF