Acute Kidney Injury And Advanced Kidney Disease in The COVID-19 Pandemic: Proceedings From A National Kidney Foundation Symposium
Mar 13, 2023
INTRODUCTION
Similar to severe acute respiratory syndrome (SARS) observed during previous coronavirus epidemics, SARS coronavirus 2 (SARS-CoV-2) uses the receptor angiotensin-converting enzyme 2 (ACE2) for cell entry.1-3 ACE2 is highly represented in lung tissues, which is why certain SARS-CoV-2 are believed to predominantly infect lower airways first. However, coronavirus disease 2019 (COVID-19) is a multisystem disease and can affect the lungs and the heart, brain, liver, and kidney. SARS-CoV-2 can also induce inflammatory cytokine releases, and the resultant “cytokine storm” or “cytokine cascade” is believed to play a major role in organ damage.
and chronic kidney disease (CKD).
the kidney injury (AKI; 3%-7%) in hospitalized patients with COVID-19.9-12 However, these cohorts had a relatively low burden of comorbid illness. More recent data indicate that AKI can occur in more than one-third of patients with COVID-19 infection. For example, a retrospective observational cohort study by Hirsch et al13 analyzed the data from 5,449 adult patients (median age, 64 years) hospitalized with COVID-19 infection from March 1, 2020, to April 5, 2020, in a New York Health System (13 hospitals). The study showed that AKI occurred in 36.6% of hospitalized patients and was particularly prominent in patients admitted to the intensive care unit or requiring invasive mechanical ventilation.13 AKI also appears to be associated with higher admission and mortality rates (Fig 1). The median urine specific gravity was high (1.020) and most patients (65.6%) had urinary sodium excretion < 35 mEq/L. Fairly high rates of proteinuria (2- 3+ positive in 42.1%) and hematuria (2+ to 3+ positive in 46.1%) were also observed. Cistanche has the function of protecting the kidney and regulating kidney function.
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OVID-19 is ongoing. Possible risk factors for AKI in patients with COVID-19 infection can include hyper-/ hypovolemia, nephrotoxins, secondary infections (ie, sepsis), hypercoagulability, direct SARS-CoV-2 virulence, and the effect of the cytokine storm. Primary causes of AKI in COVID-19 include acute tubular injury (acute tubular necrosis), collapsing glomerulopathy, rhabdomyolysis, thrombotic microangiopathy, pauci-immune glomerulonephritis, and kidney infarction.14-17 The most common pathology appears to be an acute tubular injury, whereas the most common glomerular pathology found is collapsing glomerulopathy. Initial studies suggested direct SARS-CoV- 2 viral infections in the kidney.18,19 However, other evidence points to a lack of direct renal invasion due to a possible lack of specificity for some immunohistochemical staining and the possibility that cellular components such as clathrin-coated vesicles or multivesicular bodies may have appeared as viral particles during these initial studies. Cistanche contains benzyl glycosides, which play an important role in the prevention and treatment of collapsed glomerulonephritis, rhabdomyolysis, thrombotic microangiopathy, hyperimmune glomerulonephritis, and renal infarction.
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The presence of underlying CKD has been associated with worse COVID-19 infection, although granular data for different stages of kidney disease are limited. Two studies have found that 13% and 21% of patients hospitalized for severe COVID-19 illness also had underlying CKD at the time of admission, respectively.22,23 A meta-analysis by Henry et al24 found that the presence of CKD diagnosis at the time of admission appears to be associated with an increased risk for severe COVID-19 infection. A study from a New York City hospital system found that patients with CKD and COVID-19 infection had a higher risk for mortality.25 In the study, 6.2% of the 3,391 patients with COVID-19 infection had CKD.
Patients with end-stage kidney disease (ESKD), especially those undergoing maintenance dialysis, are at higher risk for SARS-CoV-2 infection.26 When infected, patients with ESKD experience an exponentially increased risk for severe COVID-19 infection.26-29 Most recent data suggest mortality rates approximating 20% in patients with ESKD depending on their underlying comorbid conditions or geographic region. Current management recommendations for these patients are similar to those for patients with severe COVID-19 infection and also include antimetabolite reduction for transplant recipients, which centers generally perform albeit based on limited data.
RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM INHIBITORS AND NSAIDS
Debate continues as to whether patients with COVID-19 infection receiving ACE inhibitors or angiotensin receptor blockers are at increased risk for adverse outcomes.30-32 Coronaviruses such as COVID-19 bind to their target cells through ACE2, which is expressed by epithelial cells of the lung, intestine, kidney, and blood vessels. However, there is no direct evidence to support an association with these agents specifically, and stopping treatment with these agents in some patients may exacerbate comorbid cardiovascular disease or kidney disease.30,34 On the basis of current evidence, treatment with RAAS inhibitors should be continued in patients in otherwise stable conditions who are at risk for, being evaluated for, or having COVID-19.However, the use of cistanche will increase patients' resistance to kidney disease and reduce the severity of symptoms.
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There has been speculation regarding whether NSAID use increases the likelihood of contracting COVID-19 and/ or exacerbates symptoms in people with COVID-19 infection. Concern about possible negative effects of NSAIDs was raised by reports about individuals with COVID-19 receiving NSAIDs early in the course of infection and experiencing the severe disease.30,33 There has also been speculation about the possible role of an anti-inflammatory, given that the cytokine storm is believed to cause most of the negative outcomes of COVID-19. Current data show no strong evidence in favor of or disputing the use of NSAIDs with COVID-19 infection. Patients with CKD should be advised to avoid NSAIDs because they can negatively affect kidney function.
MANAGEMENT OF AKI IN COVID-19
It is essential to prevent and actively manage AKI in critically ill patients with COVID-19 infection to help decrease mortality. Supportive and critical care strategies should include adjustment of fluid balance according to volume responsiveness, hemodynamic monitoring in patients with kidney involvement, avoidance of nephrotoxins, and treatment of secondary infections and sepsis.36 Volutrauma and barotrauma could be mitigated through the application of lung-protective ventilation, which may also lower the risk for AKI by limiting ventilation-induced hemodynamic effects. Volutrauma refers to lung injury due to overdistention during mechanical ventilation, whereas barotrauma refers to physical damage to body tissues caused by a difference in pressure between a gas space inside and the surrounding fluid.37 Early and aggressive anticoagulation and efforts to inhibit cytokine release syndrome should also be considered when appropriate.
Aggressive extracorporeal ultrafiltration may precipitate or worsen hypotension among patients with COVID-19 infection with marked hemodynamic instability and/or refractory fluid overload.39,40 In these situations, initial support with continuous kidney replacement therapy (CKRT) can offer more consistency in ultrafiltration, greater hemodynamic tolerance, and fewer metabolic and osmotic flfluctuations.39 Patients with COVID-19 infection require frequent mobilization and pronation; therefore, alternative therapies, such as prolonged intermittent KRT, slow low-efficiency dialysis, and slow continuous ultra-filtration, represent a reasonable compromise between continuous and intermittent modalities.39 Prolonged intermittent KRT can be considered as an alternative to CKRT if there is not sufficient equipment to meet demand.41 Peritoneal dialysis has also been used in patients with COVID-19 and AKI during periods of increased demand.
Indications for CKRT can include oliguria with refractory hypovolemia, hyperkalemia, severe acidosis, and azotemia. Medium- or high-cutoff dialyzers, or hemadsorption devices for special cases, can be considered.39,43-45 It is also important to ensure the availability of CKRT machines and additional supplies, intensive care unit staff, special membranes, or sorbent cartridges, especially in an area of high COVID-19 incidence. Comprehensive monitoring of CKRT in critically ill patients with COVID-19 includes catheter position (after pronation), circuit patency (pressures), fluid balance, hemodynamics, and delivered diallysate/filtrate/effluent rate. Approaches to management may evolve as additional studies and evidence become available.
Emerging Therapies in AKI From COVID-19
Severely ill patients with COVID-19 infection are at elevated risk for multiorgan dysfunction due to cytokine release syndrome. Increased levels of interleukin 2 (IL-2), IL-6, IL-7, IL-8, IL-10, granulocyte-colony stimulating factor, interferon-gamma, and tumor necrosis factor have all been identified.38 A dysregulated host response to infection can lead to multisystem organ failure. This process can depend on systemic inflammation from innate immunity and possibly severe immunosuppression from adaptive immunity. Therapies such as interferon-gamma inhibitors, corticosteroids, intravenous immunoglobulin G, tumor necrosis factor blockers, and tocilizumab have been postulated to be beneficial in the treatment of cytokine storms.38 Modalities that may aid cytokine removal or modulation include cascade hemofiltration, (high volume hemofiltration), high-adsorption hemofiltration, plasmapheresis, hemoperfusion, and high-cutoff/medium-cutoff membranes.43 The aim of these interventions is to modify the cytokine-to-chemokine ratio from the tissues to the blood and/or decrease the peaks of cytokine concentrations.
The removal of cytokines through extracorporeal therapies has been an active area of study.43,45,46 Extracorporeal treatments should theoretically not interfere with experimental antibody-based therapies used in COVID-19 (eg, tocilizumab, convalescent plasma, and intravenous immunoglobulin Gs) because hemodialysis filters and hemadsorption cartridges do not remove antibodies. The size of these antibodies exceeds the size of molecules that can be removed with extracorporeal treatments. Studies indicate that certain filters can remove inflammatory markers in critically ill patients with COVID-19 infection.43,45,46 However, further research is necessary to explain the outcomes related to these therapies.
Remdesivir has been approved for severe symptoms in hospitalized patients with COVID-19. The use of redeliver in the context of AKI in COVID-19 has been an area of research. Patients with advanced kidney disease were not included in redeliver trials due to concerns about the drug’s potential toxicity among these patients. These concerns relate to remdesivir’s actions and the potential accumulation of its sulfobutylether-beta-cyclodextrin(SBECD) carrier. However, redeliver has a limited duration of treatment (5-10 days) and a relatively low concentration of SBECD carrier. Therefore, the benefits outweigh the risk in select patients with COVID-19 infection with estimated glomerular filtration rates < 30mL/min/1.73 m2.
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COVID-19 TESTING AND RISK MITIGATION IN DIALYSIS FACILITIES
Patients with advanced kidney disease, such as those with ESKD, are at increased risk for SARS-CoV-2 infection and complications of COVID-19 due to multiple risk factors, including older age, comorbid conditions (eg, cardiovascular disease, hypertension, diabetes, and chronic lung disease), and an underlying immune-compromised state. Patients receiving maintenance dialysis are at high risk for SARS-CoV-2 exposure because of their obligation to congregate frequently for prolonged periods with other patients, dialysis staff, and transportation providers.49 Patients with advanced kidney disease are also more likely than the general population to reside in skilled nursing facilities and have higher rates of hospitalization and physician visits, further increasing the risk for exposure.
CONCLUSIONS
The COVID-19 pandemic poses multiple healthcare challenges, including the management of both acute kidney disease associated with COVID-19 and COVID-19 infection in patients with underlying CKD. Data to date clearly show that AKI is common in critically ill patients with COVID-19 infection, especially those who require mechanical ventilation. Innovative approaches for KRT may be required in these patients due to concurrent complications such as volume overload and hypercoagulability. Pharmacologic and nonpharmacologic therapies for critically ill patients could be considered complementary, recognizing the possibility that no single modality could show clear evidence of survival advantage across all patients. Patients with advanced kidney disease tend to have lower transmission rates compared with the general population but in those who are infected, the mortality risk is exponentially increased. The optimal approaches for the care of these patients include the continuation of diligent mitigation procedures along with the prioritization of vaccination of patients with ESKD and dialysis unit personnel.
REFERENCES
1. Gupta A, Madhavan MV, Sehgal K, et al. Extrapulmonary manifestations of COVID-19. Nat Med. 2020;26:1017- 1032.
2. Williamson EJ, Walker AJ, Bhaskaran K, et al. Factors associated with COVID-19-related death using OpenSAFELY. Nature. 2020;584:430-436.
3. Richardson S, Hirsch JS, Narasimhan M, et al. Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City Area. JAMA. 2020;323:2052-2059.
4. Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395:1054-1062.
5. Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a Report of 72,314 cases from the Chinese Center for Disease Control and Prevention. JAMA. 2020;323(13):1239-1242.
6. Liang W, Guan W, Chen R, et al. Cancer patients in SARSCoV-2 infection: a nationwide analysis in China. Lancet Oncol. 2020;21:335-337.
7. CDC COVID-19 Response Team. Preliminary estimates of the prevalence of selected underlying health conditions among patients with coronavirus disease 2019—United States, February 12–March 28, 2020. MMWR Morb Mortal Wkly Rep. 2020;69:382-386.
8. Verity R, Okell L, Dorigatti I, et al. Estimates of the severity of coronavirus disease 2019: a model-based analysis. Lancet Infect Dis. 2020;20(6):669-677.
9. Wang D, Hu B, Hu C, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA. 2020;323:1061-1069.
10. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395:497-506.
11. Chen N, Zhou M, Dong X, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020;395: 507-513.
12. Guan WJ, Ni ZY, Hu Y, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020;382:1708- 1720.
13. Hirsch JS, Ng JH, Ross DW, et al. Acute kidney injury in patients hospitalized with COVID-19. Kidney Int. 2020;98:209- 218.
14. Mohamed MMB, Lukitsch I, Torres-Ortiz AE, et al. Acute kidney injury associated with coronavirus disease 2019 in urban New Orleans. Kidney360. 2020;1:614-622.
15. Hernandez-Arroyo CF, Varghese V, Mohamed MMB, Velez JCQ. Urinary sediment microscopy in acute kidney injury associated with COVID-19. Kidney360. 2020;1:819-823.
16. Lazareth H, Pere H, Binois Y, et al. COVID-19-related collapsing glomerulopathy in a kidney transplant recipient. Am J Kidney Dis. 2020;76(4):590-594.
17. Kissling S, Rotman S, Gerber C. Collapsing glomerulopathy in a COVID-19 patient. Kidney Int. 2020;98:228-231.
18. Puelles VG, Lütgehetmann M, Lindenmeyer MT, et al. Multi-organ and renal tropism of SARS-CoV-2. N Engl J Med. 2020;383:590-592.
19. Farkash EA, Wilson AM, Jentzen JM, et al. Ultrastructural evidence for direct renal infection with SARS-CoV-2. J Am Soc Nephrol. 2020;31:1683-1687.
20. Cassol CA, Gokden N, Larsen CP, Bourne TD. Appearances can be deceiving - viral-like inclusions in COVID-19 negative renal biopsies by electron microscopy. Kidney360. 2020;1: 824-828. 21. Calomeni E, Satoskar A, Ayoub I, Brodsky S, Rovin BH, Nadasdy T. Multivesicular bodies mimicking SARS-CoV-2 in patients without COVID-19. Kidney Int. 2020;98:233-234.
22. Petrilli CM, Jones SA, Yang J, et al. Factors associated with hospital admission and critical illness among 5279 people with coronavirus disease 2019 in New York City: prospective cohort study. BMJ. 2020;369:m1966.
23. Fair Health. The median charge for COVID-19 hospitalization ranges from $35,000 for patients aged 23-30 to $46,000 for those aged 51-60, per FAIR Health Study. Accessed October 20, 2020. https://www.fairhealth.org/press-release/chronickidney-disease-and-kidney-failure-the-most-common-comorbidityof-hospitalized-covid-19-patients
24. Henry BM, Lippi G. Chronic kidney disease is associated with severe coronavirus disease 2019 (COVID-19) infection. Int Urol Nephrol. 2020;52(6):1193-1194.
25. Yamada T, Mikami T, Chopra N, Miyashita H, Chernyavsky S, Miyashita S. Patients with chronic kidney disease have a poorer prognosis of coronavirus disease 2019 (COVID-19): an experience in New York City. Int Urol Nephrol. 2020;52(7): 1405-1406.
26. Hsu C, Weiner D, Aweh G, et al. COVID-19 among US dialysis patients: risk factors and outcomes from a national dialysis provider. Am J Kidney Dis. 2021;77(5):748-756.
27. Valeri AM, Robbins-Juarez SY, Stevens JS, et al. Presentation and outcomes of patients with ESKD and COVID-19. J Am Soc Nephrol. 2020;31:1409-1415.
28. Akalin E, Azzi Y, Bartash R, et al. Covid-19 and kidney transplantation. N Engl J Med. 2020;382:2475-2477.
29. Cohen SL, Davidson KW, Dominello AJ, et al. COVID-19 in kidney transplant recipients. Am J Transplant. 2020;20:1819- 1825.
