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COVID-19-associated acute kidney injury: consensus report of the 25th Acute Disease Quality Initiative (ADQI) Workgroup

• Mitra K. Nadim,
• Lui G. Forni,
• […]
• John A. Kellum

Extracorporeal blood purification

Biological rationale

What is the potential biological rationale for using (non-renal) EBP in critically ill patients with COVID-19?

1. 1.

   Inflammatory cytokines, DAMPs, pathogen-associated molecular patterns(PAMPs), including endotoxins and SARS-CoV-2 particles, potentially contribute to the development of multiple organ failure and mortality in critically ill patients with COVID-19.

2. 2.

   EBP techniques have been shown to remove cytokines, DAMPs and PAMPs, including endotoxins and circulating viral particles.

Rationale

EBP has been proposed as a possible adjuvant therapy for critically ill patients with COVID-19 on the basis that removal of circulating immunomodulatory mediators might prevent organ damage or mitigate organ failure in patients with COVID-19 (refs^129,130) (Fig. 4). Multiple organ failure in COVID-19 might result from the propagation of an uncontrolled host immune response involving the release of various immune mediators such as cytokines, DAMPs and PAMPs^{35,65,131,132}. In sepsis, this type of uncontrolled immune response is characterized by hyperinflammation, cytokine release, endothelial dysfunction and hypercoagulability^{66,133,134,135}. However, as discussed earlier, cytokine activation is not typically as robust in COVID-19 as it is in SARS and MERS^43,44,45, or in patients treated with chimeric antigen receptor T cell therapy or with bacterial sepsis^46,47. Moreover, the benefits and adverse effects of EBP in patients with COVID-19 have not been formally studied. Thus, we suggest that patients for whom EBP is being considered are selected carefully.

Fig. 4: Potential extracorporeal blood purification treatment options based on underlying COVID-19 pathophysiology.

Extracorporeal blood purification (EBP) has been proposed as a possible adjuvant therapy for critically ill patients with COVID-19 on the basis that removal of circulating immunomodulatory factors, that might contribute to disease processes and/or the development of multiple organ failure, might improve outcomes. Of note, the efficacy of EBP in patients with COVID-19 and/or COVID-19 AKI has not been tested, and all therapeutic options must therefore be tested in clinical trials in the context of COVID-19. EBP therapies should be considered complementary to pharmacological support. EBP therapies may also be considered in sequence or as separate entities according to current evidence or pathophysiological rationale, as changes in pathophysiology over the disease course might indicate different treatment approaches. AKI, acute kidney injury; ARDS, acute respiratory distress syndrome; COVID-19, coronavirus disease 2019; DAMPs, damage-associated molecular patterns; HCO, high cut-off; HP, haemoperfusion; MCO, medium cut-off; PAMPs, pathogen-associated molecular patterns; RRT, renal replacement therapy; TPE, therapeutic plasma exchange. Adapted from Acute Disease Quality Initiative 25, www.ADQI.org, CC BY 2.0 (https://creativecommons.org/licenses/by/2.0/).

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EBP techniques

Which EBP techniques can potentially be used to remove circulating molecules implicated in the pathophysiology of COVID-19?

1. 1.

   Haemoperfusion techniques can remove inflammatory molecules, DAMPs and PAMPs, including SARS-CoV-2 particles.

2. 2.

   Therapeutic plasma exchange (TPE) can remove inflammatory mediators and proteins associated with hypercoagulability.

3. 3.

   CRRT with surface-modified AN69 or polymethylmethacrylate membranes can remove target molecules by adsorption, whereas CRRT with medium cut-off or high cut-off membranes can remove target molecules by diffusion or convection.

Rationale

Many health-care agencies have authorized emergency use of various EBP techniques to remove molecules that are potentially causative of the immuno-inflammatory response in critically ill patients with COVID-19. However, these EBP techniques have not yet been formally studied in this patient population (Supplementary Table 2). Haemoperfusion sorbents might target the removal of virus particles, cytokines and DAMPs in patients with high endotoxin levels^{136,137,138,139,140}. In a small RCT of patients with septic shock (EUPHAS), the use of haemoperfusion was associated with improved organ function and a survival benefit¹⁴¹; however, a larger RCT (EUPHRATES) failed to confirm these findings¹³⁶. A post hoc analysis of the EUPHRATES trial demonstrated possible therapeutic survival effect in a subgroup of patients with endotoxin activity in a specific range¹⁴⁰. TPE has been shown in RCTs to improve haemodynamics, induce favourable changes in cytokine profile and improve survival in patients with septic shock^142,143. Removal of inflammatory cytokines with TPE could, in theory, confer some benefit in patients with COVID-19 with hyperinflammation and hypercoagulability¹⁴⁴. CRRT with medium cut-off, high cut-off or adsorptive membranes can remove cytokines or myoglobin and potentially prevent myoglobin-induced AKI^145,146.

Criteria for EBP use

What are possible biological and/or clinical criteria for initiating, monitoring, and discontinuing EBP in critically ill patients with COVID-19?

Recommendations

1. 1.

   No consensus exists on the use or thresholds of specific biological and clinical criteria for initiating, monitoring or discontinuing EBP in critically ill patients with COVID-19 (not graded).

Rationale

If used, EBP therapies should be selected on the basis of the pathophysiology they are designed to target. Numerous clinical criteria, including body temperature, haemodynamic status, need for vasopressor support, respiratory status and oxygenation, multiorgan failure score, cardiac and kidney function, as well as laboratory parameters such as lymphocyte counts, concentration of cytokines, ferritin, lactate dehydrogenase, D-dimers, monocytic expression of HLA, myoglobin, troponin, C-reactive protein, endotoxin activity, procalcitonin and culture results may be useful in evaluating the suitability of a patient for initiation of EBP. However, the precise indication for EBP in patients with COVID-19 remains to be determined. EBP for endotoxin removal has been generally applied for 48 consecutive hours and for 72 h for cytokine removal in studies of septic patients and in ongoing COVID-19 trials^{140,146,147,148,149}. However, there are limited data regarding the timing of initiation or duration of use of these therapies, and further studies are needed.

Research recommendations

1. 1.

   Future trials should measure the ability of EBP to remove target molecules, including assessment of their kinetics, to confirm the pathophysiological rationale for use of EBP in critically ill patients with COVID-19.

2. 2.

   Future trials should assess whether use of EBP is associated with improved short-term outcomes, including prevention and mitigation of organ failure.

3. 3.

   Future trials should assess whether combined or sequential EBP techniques can reach meaningful biological and/or clinical end points.

4. 4.

   The ability of haemoperfusion to prevent or mitigate organ failure by removal of the SARS-CoV-2 virus in patients with detected viraemia should be investigated.

5. 5.

   Future studies should validate the biological and clinical parameters that identify individuals who are likely to benefit and respond to EBP, as well as parameters for monitoring and discontinuing treatments.

6. 6.

   Future studies should evaluate TPE as an alternative for reducing hypercoagulability, hyperviscosity, and hyperinflammation in patients with COVID-19, and also assess the negative consequences of removing potentially beneficial molecules (e.g. removal of protective SARS-CoV-2 antibodies).

7. 7.

   Future studies should assess the removal of drugs and nutrients during EBP and any resulting potentially negative consequences on patient outcomes.

Conclusions

Kidney involvement following SARS-CoV-2 infection is more common than initially thought and is associated with morbidity and mortality. The pathophysiology of COVID-19 AKI is probably multifactorial — in line with the pathophysiology of other forms of AKI. Rates of COVID-19 AKI vary considerably between studies and regions, although available evidence suggests an incidence of over 20% in hospitalized patients. Many features, such as risk factors, likely mechanisms and outcomes, are shared between COVID-19 AKI and AKI arising from non-viral causes encountered in the ICU. Thus, many of the treatment recommendations, as well as preventative measures described in this Consensus Statement, are common to both. Considerations for RRT are also similar with the caveat that more aggressive anticoagulant regimes may be needed and that treatment may need to be adjusted to conserve resources in the context of a surge in COVID-19 cases. Given the potential contribution of systemic inflammation to multiorgan failure in COVID-19, the use of extracorporeal therapies may also be considered. Of note, new data on COVID-19 AKI are continually being published and these recommendations may therefore require modifications as new results become available.

Read more.
https://www.nature.com/articles/s41581-020-00356-5