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. 2024 Sep 28;12(1):85.
doi: 10.1186/s40635-024-00670-3.

Association of corticosteroid therapy with reduced acute kidney injury and lower NET markers in severe COVID-19: an observational study

Sara Bülow Anderberg  1 , Joram Huckriede  2 , Michael Hultström  3   4 , Anders Larsson  5 , Femke de Vries  2 , Miklos Lipcsey  3   6 , Gerry A F Nicolaes  2 , Robert Frithiof  3   7
Affiliations

Association of corticosteroid therapy with reduced acute kidney injury and lower NET markers in severe COVID-19: an observational study

Sara Bülow Anderberg et al. Intensive Care Med Exp. .

Abstract

Background: Acute kidney injury (AKI) is common in critical cases of coronavirus disease 2019 (COVID-19) and associated with worse outcome. Dysregulated neutrophil extracellular trap (NET) formation is one of several suggested pathophysiological mechanisms involved in the development of COVID-19 associated AKI. The corticosteroid dexamethasone was implemented as a standard treatment for severe COVID-19 as of June 2020. A sub-analysis of a prospective observational single center study was performed to evaluate the effect of corticosteroid treatment on AKI development and NET markers in critical cases of COVID-19.

Results: Two hundred and ten adult patients admitted to intensive care at a tertiary level hospital due to respiratory failure or shock secondary to SARS-CoV-2-infection between March 13th 2020 and January 14th 2021 were included in the study. Ninety-seven of those did not receive corticosteroids. One hundred and thirteen patients were treated with corticosteroids [dexamethasone (n = 98) or equivalent treatment (n = 15)], but the incidence of AKI was assessed only in patients that received corticosteroids before any registered renal dysfunction (n = 63). Corticosteroids were associated with a lower incidence of AKI (19% vs 55.8%, p < 0.001). Fewer patients demonstrated detectable concentrations of extracellular histones in plasma when treated with corticosteroids (8.7% vs 43.1%; p < 0.001). Extracellular histones and in particular non-proteolyzed histones were observed more frequently with increasing AKI severity (p < 0.001). MPO-DNA was found in lower concentrations in patients that received corticosteroids before established renal dysfunction (p = 0.03) and was found in higher concentrations in patients with AKI stage 3 (p = 0.03). Corticosteroids did not ameliorate established AKI during the first week of treatment.

Conclusion: Corticosteroid treatment in severe COVID-19 is associated with a lower incidence of AKI and reduced concentrations of NET markers in plasma.

Keywords: Acute kidney injury; COVID-19; Corticosteroids; Histones; MPO-DNA; NETs.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Patient groups used to investigate the effect of corticosteroid on acute kidney injury incidence. Two hundred and twenty-two adult patients were included between March 13th 2020 and January 14th 2021 due to suspected or confirmed SARS-CoV 2 infection with respiratory failure and/or shock at time of admission to intensive care. Due to unconfirmed viral infection, withdrawal of consent, renal transplant or missing plasma and urine samples 210 patients remained in the cohort. Corticosteroid (CS) treatment entailed dexamethasone 6 mg daily or equivalent treatment. Ninety-seven patients did not receive corticosteroids. Two of these patients were excluded due to missing baseline creatinine values. One hundred and thirteen patients received corticosteroids; 98 patients dexamethasone and 15 patients other forms. Only patients that had therapy initiated prior to AKI development were included in the final comparison (n = 63). Acute kidney injury (AKI) was diagnosed according to the KDIGO creatinine criteria exclusively
Fig. 2
Fig. 2
Patient groups used in investigating the effect of corticosteroids on markers of cellular damage and neutrophil activity including extracellular trap formation. Two hundred and twenty-two adult patients were included between March 13th 2020 and January 14th 2021 due to suspected or confirmed SARS-CoV 2 infection with respiratory failure and/or shock at time of admission to intensive care. Due to unconfirmed infection, withdrawal of consent, renal transplantation or missing plasma and urine samples 210 patients remained in the cohort. Corticosteroid (CS) treatment entailed dexamethasone 6 mg daily or equivalent medication. Ninety-seven patients did not receive corticosteroids. One hundred and thirteen patients received these drugs; 98 patients dexamethasone and 15 patients other forms. Twenty-nine patients were excluded due to start of corticosteroids after blood and urine sampling and an additional nine patients due to missing sampling dates
Fig. 3
Fig. 3
Corticosteroids and their association with acute kidney injury incidence during severe COVID-19. Acute kidney injury (AKI) was diagnosed according to the KDIGO creatinine criteria exclusively in the present analysis. Corticosteroid (CS) treatment initiated prior to any registered renal dysfunction in patients with critical COVID-19 was associated with a lower frequency of AKI development (p < 0.001). Fifty-three (55.8%) patients not treated with corticosteroids developed AKI. In order of severity, 33 (34.7%) individuals developed stage 1, 9 (9.5%) stage 2 and 11 (11.6%) stage 3. Fifty-one (81.0%) patients did not develop AKI in the group treated with corticosteroids. The patients that did were distributed as follows; 7 (11.1%) patients reached stage 1, 3 (4.8%) stage 2 and 2 (3.2%) stage 3. Fisher’s exact test was used to compare treatment groups due to small numbers
Fig. 4
Fig. 4
Corticosteroids and their association with extracellular histones in plasma during severe COVID-19. The effect of corticosteroids (CS), dexamethasone 6 mg daily or equivalent, on detectable extracellular histones, histone core protein 3 (H3) concentration and proteolysis of histones in plasma was evaluated in patients admitted to intensive care due to severe COVID-19. Samples were collected adjacent to admission and it was ensured that corticosteroid treatment was started prior to sampling. In this case any renal impairment was disregarded. A Corticosteroids were associated with reduced expression of extracellular histones in plasma [8.7% (n = 6) vs 43.1% (n = 53)] and if detected they were in the proteolyzed (cleaved) form (p < 0.001). Non-cleaved and cleaved histones were observed in 24.4% (n = 30) and 18.7% n = 23 of non-treated patients respectively. Fisher’s exact test was used to compare treatment groups. B H3 could be measured in 26 (21.1%) patients (n = 123) that were not treated with corticosteroids and in six (8.7%) patients (n = 69) that were. All individuals with H3 concentrations above 0.0 ng/ml were located within the fourth quartile in both respective treatment groups resulting in medians of 0.0 ng/ml and interquartile ranges of 0.0 ng/ml. Using the Mann Whitney U test, it was found that the groups were significantly different from one another. The highest observed concentrations were 3.6 µg/ml and 0.8 µg/ml, respectively (p = 0.02)
Fig. 5
Fig. 5
Corticosteroids implemented before acute kidney injury development and their association with extracellular histones and myeloperoxidase-DNA in plasma during severe COVID-19. The effect of corticosteroid treatment (CS), dexamethasone 6 mg daily or equivalent, was investigated on detectable extracellular histones, proteolysis of these histones and histone core protein 3 (H3) concentration in plasma in severe COVID-19 cases. Samples were collected adjacent to admission. It was ensured that corticosteroid treatment was started prior to any acute kidney injury development in the treated group (n = 63) of which 49 patients had plasma analyzed. Ninety-four patients not treated with corticosteroids had samples analyzed. Acute kidney injury was diagnosed according to KDIGO creatinine criteria only. A Treatment was associated with a reduced expression of extracellular histones in plasma [2% (n = 1) vs 47.9% (n = 45)] (p < 0.001) according to Fisher’s exact test. Intact (non-cleaved) and proteolyzed (cleaved) histones were observed in 23.4% (n = 22) and 24.5% (n = 23) of non-treated patients, respectively. B H3 concentration was estimated to 0.0 ng/ml in all of the patients treated with corticosteroids before AKI development. Twenty-two individuals had H3 concentrations above 0.0 ng/ml in the non-treated group. The groups were different according to a Mann Whitney U test using ranks. (C) MPO-DNA concentration, a marker of neutrophil extracellular trap formation, was measured in arbitrary units (AU) in plasma. The marker was observed in higher concentrations in patients without treatment (101.1 (27.7) vs 92.2 (26.0) AU) and were statistically different according to a Mann Whitney U test
Fig. 6
Fig. 6
Extracellular histones and myeloperoxidase-DNA in plasma and their association with acute kidney injury severity in critical cases of COVID-19. The association between acute kidney injury stage and extracellular histones (n = 189) and MPO-DNA (n = 183) was examined. Acute kidney injury (AKI) was diagnosed according to KDIGO creatinine criteria solely. A Extracellular histones were detected in plasma of patients admitted to the ICU due to severe COVID-19 using a Western blot technique. If detected they were further classified as proteolyzed or not (cleaved or non-cleaved) by their molecular weight. Histones, in particular in the non-cleaved form, were associated with more severe stages of AKI (p < 0.001) according to a Fisher’s exact test. Extracellular histones were observed in 20 (25%) patients with no observed renal dysfunction of which the minority were non-cleaved [n = 6 (7.5%)]. Sixteen (25.4%) patients with AKI stage 1 had detectable histones in plasma and non-cleaved histones were observed in 7 (11.1%) patients. Nearly half of patients with AKI stage 2 [n = 10 (47.6%)] had detectable extracellular histones in plasma. Non-cleaved histones were found in 4 (19.0%) patients. In AKI stage 3 extracellular histones were observed in 11 (44.0%) patients and these were all in the non-cleaved form. B Myeloperoxidase complexed with DNA (MPO-DNA) was estimated in plasma from samples collected adjacent to ICU admission. An increase was observed across AKI stages. A Kruskal Wallis analysis indicated significant differences between groups and Dunn’s post hoc analysis demonstrated a significantly higher concentration in patients with AKI stage 3 compared to individuals with no observed renal dysfunction
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References

    1. Khwaja A (2012) KDIGO clinical practice guidelines for acute kidney injury. Nephron Clin Pract 120:c179–c184 - PubMed
    1. Silver SA, Beaubien-Souligny W, Shah PS, Harel S, Blum D, Kishibe T, Meraz-Munoz A, Wald R, Harel Z (2021) The prevalence of acute kidney injury in patients hospitalized with COVID-19 infection: a systematic review and meta-analysis. Kidney Med 3:83-98.e81 - PMC - PubMed
    1. Hultström M, Lipcsey M, Wallin E, Larsson IM, Larsson A, Frithiof R (2021) Severe acute kidney injury associated with progression of chronic kidney disease after critical COVID-19. Crit Care 25:37 - PMC - PubMed
    1. Luther T, Bülow-Anderberg S, Larsson A, Rubertsson S, Lipcsey M, Frithiof R, Hultström M (2021) COVID-19 patients in intensive care develop predominantly oliguric acute kidney injury. Acta Anaesthesiol Scand 65:364–372 - PMC - PubMed
    1. Legrand M, Bell S, Forni L, Joannidis M, Koyner JL, Liu K, Cantaluppi V (2021) Pathophysiology of COVID-19-associated acute kidney injury. Nat Rev Nephrol 17:751–764 - PMC - PubMed

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