COVID-19 And The Multisystem Inflammatory Syndrome in Children: How Vulnerable Are The Kidneys?
Mar 14, 2023
Yu et al. reported that the Ph.D. inhibitor L-mimosine exerted dual action on CKD progression in a rat model of subtotal nephrectomy. Midterm administration of L-mimosine inhibited renal fibrosis, macrophage infiltration, and CKD progression; however, the long-term administration of L-mimosine worsened all these parameters. Therefore, the protective effect of HIF activation against CKD progression might depend on the timing of HIF-PHI administration. In contrast, a recent study reported that in patients with CKD at stages 3 to 5 receiving either roxadustat or placebo, there was no significant between-group difference in the progression of CKD, as measured by the rate of change in estimated glomerular filtration rate over time.
FGF23 is mainly produced in osteocytes to regulate phosphate homeostasis. Plasma levels of FGF23 are elevated in patients with CKD, which is an independent risk factor for end-stage renal disease and cardiovascular mortality. HIF activation, as well as EPO and iron deficiency, can increase FGF23 mRNA transcription with increased posttranscriptional cleavage. Vadadustat increased plasma total and intact FGF23 levels in non-CKD mice. In contrast, in CKD mice, vadadustat diminished the elevated plasma levels of total and intact FGF23, which is inconsistent with previous findings. According to the authors, vadadustat reduced plasma FGF23 levels in the CKD model owing to the amelioration of kidney function and impaired iron utilization. However, the mechanism by which HIF-PHIs affect FGF23 regulation in CKD still needs to be clarified.
Overall, the study by Handel et al. provides new information on the effects of HIF-PHIs in improving the anemia of CKD, which could be useful in current clinical practice. Furthermore, despite its experimental nature, the study provides future directions for research on the action of HIF-PHIs in patients with CKD.
Cistanche is a traditional Chinese herb that has been used for centuries to treat various diseases. It has been scientifically proven to possess anti-inflammatory, anti-aging, and antioxidant properties. Studies have shown that Cistanche is beneficial for patients suffering from kidney disease. The active ingredients of Cistanche are known to reduce inflammation, improve kidney function and restore impaired kidney cells. Thus, integrating Cistanche within a kidney disease treatment plan can offer great benefits to patients in managing their condition.
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Cistanche helps to reduce proteinuria, lowers BUN and creatinine levels, and decreases the risk of further kidney damage. In addition, Cistanche also helps reduce cholesterol and triglyceride levels which can be dangerous to patients suffering from kidney disease.
Cistanche's antioxidant and anti-aging properties help to protect the kidneys from oxidation and damage caused by free radicals. This improves kidney health and reduces the risks of developing complications. Cistanche also helps to boost the immune system, which is essential in fighting off kidney infections and promoting kidney health.
By combining traditional Chinese herbal medicine and modern western medicine, those suffering from kidney disease can have a more comprehensive approach to treating the condition and improving their quality of life. Cistanche should be used as part of a treatment plan but is not to be used as an alternative to conventional medical treatments.
DISCLOSURE
REFERENCES
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2.Kautz L, Jung G, Valore EV, et al. Identification of erythroferrone as an erythroid regulator of iron metabolism. Nat Genet. 2014;46:678–684.
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4.Hanudel MR, Wong S, Jung G, et al. The amelioration of chronic kidney disease-associated anemia by vadadustat in mice is not dependent on erythroferrone. Kidney Int. 2021;100:79–89.
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7. Yu X, Fang Y, Liu H, et al. The balance of beneficial and deleterious effects of hypoxia-inducible factor activation by prolyl hydroxylase inhibitor in rat remnant kidney depends on the timing of administration. Nephrol Dial Transplant. 2012;27:3110–3119.
8. Coyne DW, Roger SD, Shin SK, et al. Roxadustat for CKD-related anemia in non-dialysis patients. Kidney Int Rep. 2021;6:624–635.
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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.
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 have 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. 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. 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. 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%. In addition, up to one-third of those who survived following renal replacement therapy did not achieve full recovery of kidney function at the time of discharge.
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. 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. 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. 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 patients with MIS-C are older (average age, >7 years), have intense inflammation, have a 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.
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%).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 impaired kidney function. Nevertheless, none of the patients with MIS-C required renal replacement therapy, and 9 of 10 patients had a 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 kidney injury in pediatric patients with COVID-19 and MIS-C is not severe in most instances.
DISCLOSURE
All the authors declared no competing interests.
REFERENCES
1.Fisher M, Neugarten J, Bellin E, et al. AKI in hospitalized patients with and without COVID-19: a comparison study. J Am Soc Nephrol. 2020;31:2145–2157.
2.Hoste EAJ, Bagshaw SM, Bellomo R, et al. Epidemiology of acute kidney injury in critically ill patients: the multinational AKI-EPI study. Intensive Care Med. 2015;41:1411–1423.
3. Bhasin B, Veitla V, Dawson AZ, et al. Acute kidney injury in hospitalized patients with COVID-19 and seasonal influenza: a comparative analysis. Kidney 360. 2021;2:619–628.
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5. Basalely 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;100:138–145.
6.Bjornstad EC, Krallman KA, Askenazi D, et al. Preliminary assessment of acute kidney injury in critically ill children associated with SARSCoV-2 infection: a multicenter cross-sectional analysis. Clin J Am Soc Nephrol. 2021;16:446– 448.
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