MODERATORS: Luuk Hilbrands, NL – Ron Gansevoort, NL

The epidemiology of AKI in COVID-19: clinical consequences.
PRESENTER: Nicholas Selby, UK
PANELLIST:   Eric Hoste, BE

Mechanisms how SARS-Cov2 causes kidney damage: therapeutic implications.
PRESENTER: Tobias Huber, DE
PANELLIST:   Bjorn Meijers, BE

e-seminar Summary

Written by Jasna Trbojevic-Stankovic
Reviewed by Ronald Gansevoort

The coronavirus COVID-19 pandemic presented an unprecedented challenge to healthcare services worldwide in the previous months. The disease afflicts multiple organ systems and may also target kidney cells and cause acute kidney injury. On the other hand, patients with existing chronic kidney disease (CKD) are at a much higher risk for severe illness when infected. In response to the COVID-19 pandemic the European Renal Association- European Dialysis Transplantation Association (ERA-EDTA) established the European Renal Association COVID-19 Database (ERACODA) in March 2020 to investigate the clinical course, outcomes, and risk factors for mortality in kidney replacement patients with COVID-19. Related to this initiative and to spread the finest quality scientific knowledge and deliver the latest findings to the nephrology community, ERA-EDTA has organized a series of e-seminars on practical COVID-19 related aspects relevant to renal professionals. The second ERACODA seminar is dedicated to the COVID-related aspects of acute kidney injury (AKI) with professors Luuk Hilbrands and Ron Gansevoort as moderators, professors Nicholas Selby and Tobias Huber as presenters, and professors Eric Hoste and Bjorn Meijers as panelists.

The epidemiology of AKI in COVID-19: Clinical consequences

Presenter: Prof. Nicholas Selby (University of Nottingham, United Kingdom)

Panelist: Prof. Eric Hoste (Ghent University Hospital, Belgium)

Early reports at the onset of the COVID-19 pandemic indicated that rates of AKI in COVID-19 patients were negligible. One case series analysis even reported an incidence of 0%. However, later growing evidence demonstrated that AKI is notably prevalent, particularly among severe COVID-19 cases admitted to intensive care units (ICUs) (1, 2).

Still, the reported rates of AKI are remarkably variable. For instance, a systematic review of 20 studies that included more than 13,000 mostly hospitalized COVID-19 patients showed that the prevalence of AKI is 17%, with about 5% of all patients requiring the use of renal replacement therapy (RRT). The subgroup analysis, however, revealed substantial regional differences with AKI prevalence ranging between 19% and 57% in Europe and United States (3). Such differences likely resulted from different definitions of AKI and the populations studied. Another study, which defined AKI according to the KDIGO criteria, confirmed such assumptions and found that of 5,449 hospitalized COVID-19 patients, AKI developed in 36.6%. The peak stages of AKI were stage 1 in 46.5%, stage 2 in 22.4%, and stage 3 in 31.1% (4). Several reports also indicate that between 61% and 76% of COVID-19 patients admitted to the ICU develop AKI and that between 26% and 45% of them require RRT (4-6).  COVID-19-positive patients are twice as likely to develop AKI compared to the COVID-19–negative hospitalized patients (7). Another study reported that about 75% of patients with COVID-19 pneumonia had renal involvement on admissions: 65.8% presented with proteinuria, 41.7% with hematuria, and 4.7% with AKI (8).

Independent risk factors for AKI include older age, diabetes mellitus, cardiovascular disease, black race, hypertension, and need for mechanical ventilation and vasopressor medications. As shown in Figure 1, most cases develop AKI early in the course, usually arriving with AKI or developing it within 24 hours of admission. Then, the second peak occurs typically after eight or more days due to clinical deterioration (e.g. secondary sepsis) or around the time of mechanical ventilation (4).

Figure 1. The number of patients with an initial diagnosis of AKI, by hospital day of admission (4)

As expected, AKI is associated with significantly higher mortality among COVID-19 patients, with a pooled odds ratio of 15.27 compared with patients without AKI (3).

The first wave of COVID-19 (up to August 31, 2020) was particularly dramatic for kidney disease patients. Fortunately, it seems that the pattern is changing in the second wave as recent Intensive Care National Audit & Research Centre (ICNARC) report revealed a lower proportion of COVID-19 patients requiring RRT, lower duration of RRT, and the lower number of mechanical ventilation within the first 24 hours of admission compared to first wave (Figure 2) (9).  Increased awareness, new guidelines, timely fluid status management, and the use of dexamethasone are all responsible for these positive outcomes in the second wave (10, 11).

Figure 2. Patients with confirmed COVID-19 and outcome received. ICNARC report (9)

Much is still unknown about what might be the long-term consequences in COVID-19 patients who had AKI. Bowe et al noted that 47% of their patients had partial or incomplete AKI recovery at discharge – which highlights the need for careful monitoring and post-AKI care to reduce the risk of AKI recurrence and mitigate the risk of long-term complications, including potential development or progression of chronic kidney disease (CKD) (12).

Mechanisms how SARS-Cov2 causes kidney damage: Therapeutic implications

Presenter: Prof. Tobias Huber (University Medical Center Hamburg-Eppendorf, Germany)

Panelist: Prof. Bjorn Meijers (University Hospitals Leuven, Belgium)

Patients dying from COVID-19 have a higher number of comorbidities, which might be associated with tropism of SARS-CoV-2 beyond the respiratory tract, also including the kidneys, liver, heart, and brain. Such multiorgan tropism influences the course of COVID-19 disease and additionally aggravates preexisting conditions. After the respiratory tract, the kidneys exhibit the highest viral loads compared to other organs. This can be explained by the higher presence of SARS-CoV-2 infection adhesion and facilitators genes throughout different kidneys compartments.

Renal tropism of SARS-CoV-2 can be easily detected with the use of in situ hybridizations (spatially resolved viral RNA detection) and indirect immunofluorescence (spatially resolved viral protein detection) with confocal microscopy (Figure 3) (13).

Figure 3. Multiorgan SARS-CoV-2 tropism and spatially resolved affinity for kidney cells (13)

In a post-mortem analysis of 63 COVID-19 patients with a respiratory infection, SARS-CoV-2 RNA was detected in the kidneys of 60% of patients, predominantly in elderly males with a high number of comorbidities. In 32 patients who developed AKI, viral RNA was found in 72%. By contrast, patients without AKI showed a lower frequency of SARS-CoV-2 renal tropism, with viral RNA only found in three (43%) of seven patients. Renal tropism was also associated with a reduction in patient’s survival time. These findings indicate that SARS-CoV-2 renal tropism is associated with disease severity, development of AKI, and premature death. When SARS-CoV-2 was isolated from an autopsied kidney, it produced a 1000-times increase in viral RNA after 48 hours of cell infection in vitro, thus confirming an active postmortem presence of infective virus in the kidney. Furthermore, patient-derived SARS-CoV-2 is also able to replicate in non-human primate kidney tubular epithelial cells – the main cellular target of AKI (14).

Proximal tubules can be considered as a specific target for SARS-CoV-2 infection. To date, three pathophysiological mechanisms including viral entry and infection, cytokine-mediated injury, and hemodynamic factors, and ischemia, appear to be most plausible to cause proximal tubular dysfunction and kidney injury in COVID-19 patients. While each of them can explain tubular dysfunction, it is also possible that these factors coexist and interact with each other during the complex clinical course of COVID-19 (15). Noteworthy, COVID-19 patients without urinary abnormalities (i.e. proteinuria, hematuria) have a much lower risk of ICU admission as well as the risk of death compared to those with moderate and severe urinary abnormalities. Since early detection of urine abnormalities may predict kidney complications in COVID-19 patients, all patients should be routinely screened with simple and inexpensive urinary dipstick tests before admission to the hospital (16).

References

1. Wang L, Li X, Chen H, et al. Coronavirus Disease 19 Infection Does Not Result in Acute Kidney Injury: An Analysis of 116 Hospitalized Patients from Wuhan, China. Am J Nephrol. 2020;51(5):343-348. doi:10.1159/000507471

2. Silver SA, Clark EG, Hiremath S. Misleading Numbers: Is the Risk of Acute Kidney Injury with COVID-19 Truly This Low?. Am J Nephrol. 2020;51(7):574-575. doi:10.1159/000508088

3. Robbins-Juarez SY, Qian L, King KL, et al. Outcomes for Patients With COVID-19 and Acute Kidney Injury: A Systematic Review and Meta-Analysis. Kidney Int Rep. 2020;5(8):1149-1160. Published 2020 Jun 25. doi:10.1016/j.ekir.2020.06.013

4. Hirsch JS, Ng JH, Ross DW, et al. Acute kidney injury in patients hospitalized with COVID-19. Kidney Int. 2020;98(1):209-218. doi:10.1016/j.kint.2020.05.006

5. Mohamed MMB, Lukitsch I, Torres-Ortiz AE, et al. Acute Kidney Injury Associated with Coronavirus Disease 2019 in Urban New Orleans. Kidney360. 2020;1(7):614-622. doi: https://doi.org/10.34067/KID.0002652020

6. Chan L, Chaudhary K, Saha A, et al. AKI in Hospitalized Patients with COVID-19. J Am Soc Nephrol. 2021;32(1):151-160. doi:10.1681/ASN.2020050615

7. Kolhe NV, Fluck RJ, Selby NM, Taal MW. Acute kidney injury associated with COVID-19: A retrospective cohort study. PLoS Med. 2020;17(10):e1003406. Published 2020 Oct 30. doi:10.1371/journal.pmed.1003406

8. Pei G, Zhang Z, Peng J, et al. Renal Involvement and Early Prognosis in Patients with COVID-19 Pneumonia. J Am Soc Nephrol. 2020;31(6):1157-1165. doi:10.1681/ASN.2020030276

9. Intensive Care National Audit & Research Centre (ICNARC). ICNARC report on COVID-19 in critical care: England, Wales and Northern Ireland. https://www.icnarc.org/Our-Audit/Audits/Cmp/Reports Updated March 19, 2021. Accessed March 22, 2021.

10. Selby NM, Forni LG, Laing CM, et al. Covid-19 and acute kidney injury in hospital: summary of NICE guidelines. BMJ. 2020;369:m1963. Published 2020 May 26. doi:10.1136/bmj.m1963

11. RECOVERY Collaborative Group, Horby P, Lim WS, et al. Dexamethasone in Hospitalized Patients with Covid-19. N Engl J Med. 2021;384(8):693-704. doi:10.1056/NEJMoa2021436

12. Bowe B, Cai M, Xie Y, Gibson AK, Maddukuri G, Al-Aly Z. Acute Kidney Injury in a National Cohort of Hospitalized US Veterans with COVID-19. Clin J Am Soc Nephrol. 2020;16(1):14-25. doi:10.2215/CJN.09610620

13. Puelles VG, Lütgehetmann M, Lindenmeyer MT, et al. Multiorgan and Renal Tropism of SARS-CoV-2. N Engl J Med. 2020;383(6):590-592. doi:10.1056/NEJMc2011400

14. Braun F, Lütgehetmann M, Pfefferle S, et al. SARS-CoV-2 renal tropism associates with acute kidney injury. Lancet. 2020;396(10251):597-598. doi:10.1016/S0140-6736(20)31759-1

15. Braun F, Huber TB, Puelles VG. Proximal tubular dysfunction in patients with COVID-19: what have we learnt so far? Kidney Int. 2020;98(5):1092-1094. doi:10.1016/j.kint.2020.09.002

16. Gross O, Moerer O, Weber M, Huber TB, Scheithauer S. COVID-19-associated nephritis: early warning for disease severity and complications?. Lancet. 2020;395(10236):e87-e88. doi:10.1016/S0140-6736(20)31041-2

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