Restore the Balance in the ICU

The critical role of nephrologists in restoring immune homeostasis

AKI in the ICU: An Inflammatory Imbalance

Systemic inflammation in severe COVID-19 can cause acute kidney injury (AKI).

ICU patients with AKI are at risk for^1-3

Dialysis or continuous renal replacement therapy (CRRT)
Dialysis dependency
Extended length of stay in the ICU
Damage to other organs
Mortality

AKI is common in patients with severe COVID-19 and is linked
to poor outcomes

In a study of hospitalized patients with COVID-19, 46% developed AKI.⁴

19% of patients with AKI
required dialysis

50% of patients with AKI
died

Interestingly, the morphological and immunologic characteristics of COVID-19–associated AKI are similar to those of sepsis-associated AKI.⁵

Regardless of the trigger, damaging systemic inflammation can cause AKI

When the body initiates inflammation to contain invasive pathogens and repair injury, the balance between pro- and anti-inflammatory cells and signals must be tightly calibrated to restore homeostasis and minimize collateral damage to tissues and organs.⁶

Uncontrolled inflammation, caused by imbalances in proinflammatory and anti-inflammatory signals, can be triggered by viral or bacterial infection, trauma, or surgery.^7-9 COVID-19, like sepsis, can cause systemic inflammation.^5,6

The kidneys and lungs are particularly sensitive to damage caused by systemic inflammation. Injury to these organs (eg, AKI or acute respiratory distress syndrome [ARDS], respectively) can initiate and perpetuate a vicious cycle of damaging systemic inflammation.^10,11

Rising Above the Storm

Critical effector cells are the source of systemic inflammation.

Leukocytes—neutrophils and monocytes—are critical effector cells that drive systemic inflammation

Neutrophils and monocytes secrete a range of proinflammatory cytokines that initiate and propagate imbalanced immune responses.⁶ When dysregulated, neutrophils and monocytes can cause direct tissue damage.¹²

Elevation of specific cytokines and other inflammatory biomarkers predicts mortality in patients with COVID-19.¹³ These biomarkers decline as immune homeostasis is restored in patients who recover.¹³

Cytokine-directed approaches, which often target a single cytokine, have had inconsistent clinical benefit

Cytokine-directed approaches do not target critical effector cells; they target downstream mediators.^14,15 Removing cytokines downstream without stopping the creation of additional cytokines does not produce consistent clinical outcomes.^14,15

Many different cytokines are abnormally elevated during COVID-19–associated systemic inflammation, creating what is often referred to as a cytokine storm.^6,13 Therapies targeting an individual cytokine pathway, such as interleukin-6, have not consistently reduced mortality in clinical trials of patients with COVID-19.¹⁵ Adsorption of cytokines via standard extracorporeal blood purification can remove both pro- and anti-inflammatory cytokines, which may fail to correct the imbalance between these types of mediators. Consequently, cytokine filters also have shown limited and inconsistent clinical benefit in patients with sepsis or COVID-19.^15,16

Targeting the cellular sources of systemic inflammation—neutrophils and monocytes—rather than downstream cytokine signaling, is an alternative therapeutic approach that may restore balance to immune responses, initiating renal repair and recovery

The cytokines targeted by current therapies are continuously produced by critical effector cells that remain hyperactivated.¹⁴ Targeting effector cells to balance the immune response may initiate repair and recovery.^12,14 Immunomodulation of neutrophils and monocytes may be a therapeutic strategy to stop systemic inflammation at the source.^12,14

Restoring the Balance

Clinical data for targeting the cellular source of systemic inflammation were presented at ASN.

The selective cytopheretic device (SCD) is a cell-directed extracorporeal therapeutic approach to address systemic inflammation

The SCD

Removes proinflammatory leukocytes from circulation and reduces plasma levels of inflammatory cytokines¹⁴
Is being investigated as an adjunctive therapeutic option for certain critically ill patients (eg, sepsis-associated AKI, COVID-19)^12,14
Can be connected in series with standard CRRT devices with regional citrate anticoagulation (RCA)¹⁷

Recent data from a study of the SCD in adults with severe COVID-19 and AKI and/or ARDS was presented virtually at ASN Kidney Week 2021

Patients in the ICU with COVID-19, AKI requiring CRRT, and ARDS requiring mechanical ventilation¹⁸
No adverse events related to the SCD or RCA¹⁸
No leukopenia or neutropenia was observed¹⁸
SCD-treated patients had lower mortality than a contemporaneous control population and experienced biomarker improvements consistent with restoring immune homeostasis¹⁸

View the ASN poster, presented at Kidney Week 2021

ASN 2021 poster

SCD Treatment in COVID-19 ICU Patients With ARDS and AKI May Improve Clinical Outcomes

Interested in our upcoming adult pivotal study or other related research?

Interested in SCD clinical trials? Want to learn more? Contact us for more information.

References: 1. Cerdá J, Liu KD, Cruz DN, et al. Promoting kidney function recovery in patients with AKI requiring RRT. Clin J Am Soc Nephrol. 2015;10(10):1859-1867. https://doi.org/10.2215/CJN.01170215
2. Doyle JF, Forni LG. Acute kidney injury: short-term and long-term effects. Crit Care. 2016;20(1):188. https://doi.org/10.1186/s13054-016-1353-y
3. Tumlin JA, Galphin CM, Tolwani AJ, et al. A multi-center, randomized, controlled, pivotal study to assess the safety and efficacy of a selective cytopheretic device in patients with acute kidney injury. PLoS One. 2015;10(8):e0132482. https://doi.org/10.1371/journal.pone.0132482
4. Chan L, Chaudhary K, Saha A, et al. AKI in hospitalized patients with COVID-19. J Am Soc Nephrol. 2021;32(1):151-160. https://doi.org/10.1681/ASN.2020050615
5. Alexander MP, Mangalaparthi KK, Madugundu AK, et al. Acute kidney injury in severe COVID-19 has similarities to sepsis-associated kidney injury: a multi-omics study. Mayo Clinic Proceedings. 2021;96(10):2561-2575. https://doi.org/10.1016/j.mayocp.2021.07.001
6. Fajgenbaum DC, June CH. Cytokine storm. N Engl J Med. 2020;383(23):2255-2273. https://doi.org/10.1056/NEJMra2026131
7. D’Elia RV, Harrison K, Oyston PC, Lukaszewski RA, Clark GC. Targeting the “cytokine storm” for therapeutic benefit. Clin Vaccine Immunol. 2013;20(3):319-327. https://doi.org/10.1128/CVI.00636-12
8. Singbartl K, Formeck CL, Kellum JA. Kidney-immune system crosstalk in AKI. Semin Nephrol. 2019;39(1):96-106. https://doi.org/10.1016/j.semnephrol.2018.10.007
9. Zhang WR, Garg AX, Coca SG, et al. Plasma IL-6 and IL-10 concentrations predict AKI and long-term mortality in adults after cardiac surgery. J Am Soc Nephrol. 2015;26(12):3123-3132. https://doi.org/10.1681/ASN.2014080764

10. Singbartl K, Bishop JV, Wen X, et al. Differential effects of kidney-lung cross-talk during acute kidney injury and bacterial pneumonia. Kidney Int. 2011;80(6):633-644. https://doi.org/10.1038/ki.2011.201
11. Park BD, Faubel S. Acute kidney injury and acute respiratory distress syndrome. Crit Care Clin. 2021;37(4):835-849. https://doi.org/10.1016/j.ccc.2021.05.007
12. Goldstein SL, Askenazi DJ, Basu RK, et al. Use of the selective cytopheretic device in critically ill children. Kidney Int Rep. 2021;6(3):775-784. https://doi.org/10.1016/j.ekir.2020.12.010
13. Abers MS, Delmonte OM, Ricotta EE, et al. An immune-based biomarker signature is associated with mortality in COVID-19 patients. JCI Insight. 2021;6(1):144455. https://doi.org/10.1172/jci.insight.144455
14. Yessayan L, Szamosfalvi B, Napolitano L, et al. Treatment of cytokine storm in COVID-19 patients with immunomodulatory therapy. ASAIO J. 2020;66(10):1079-1083. https://doi.org/10.1097/MAT.0000000000001239
15. Rizvi MS, Gallo De Moraes A. New decade, old debate: blocking the cytokine pathways in infection-induced cytokine cascade. Crit Care Explor. 2021;3(3):e0364. https://doi.org/10.1097/CCE.0000000000000364
16. Ostermann M, Koyner JL. Extracorporeal blood purification is appropriate in critically ill patients with COVID-19 and multi-organ failure: commentary. Kidney360. Published online August 19, 2021:10.34067/KID.0005242021. https://doi.org/10.34067/KID.0005242021
17. Tumlin JA, Chawla L, Tolwani AJ, et al. The effect of the selective cytopheretic device on acute kidney injury outcomes in the intensive care unit: a multicenter pilot study. Semin Dial. 2013;26(5):616-623. https://doi.org/10.1111/sdi.12032
18. Yessayan LT, Neyra JA, Westover A, Szamosfalvi B, Humes HD. SCD treatment in COVID-19 ICU patients with ARDS and AKI may improve clinical outcomes. Poster presented at the: American Society of Nephrology Kidney Week; November 4-7, 2021; Virtual Meeting.