MODERATOR: Luuk Hilbrands, NL

Is CKD the key risk factor for COVID-19 mortality?
PRESENTER: Ron Gansevoort, NL
PANELLIST: Alberto Ortiz, ES

Risk factors for COVID-19 mortality in the CKD population. Are they different from the general population?
PRESENTER: Marlies Noordzij, NL
PANELLIST: Cecile Couchoud, F

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 (1). In the following seven months valuable data has been gathered of 2,017 patients from 31 countries, mainly in Europe. Related to this initiative and in an effort 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 first ERACODA seminar is dedicated to the relationship between CKD and COVID-19 with professor Luuk Hilbrands as a moderator, professor Ron Gansevoort, and doctor Marlies Noordzij as presenters, and professor Alberto Ortiz and doctor Cecile Couchoud as panelists.

Is CKD the key risk factor for COVID-19 mortality?
The first report of COVID-19 released in January 2020 identified diabetes, hypertension, and cardiovascular disease as risk factors for severe illness. The current picture, however, differs significantly from initial reports. The study by Ko et al. identified early-stage CKD to be associated with a higher risk for hospitalization than hypertension, diabetes, coronary artery disease, chronic respiratory disease, history of stroke, and moderate obesity based on an analysis of 5,416 cases of COVID-19 in community-dwelling adults in the United States (2). Mortality risk from COVID-19 in diabetic patients was also associated with the presence and severity of CKD, and in type 1 diabetes increased significantly when glomerular filtration rate (GFR) dropped below 60 mL/min (3). Further studies confirmed that individuals with underlying CKD are particularly vulnerable to COVID-19-related critical illness and a higher mortality rate (4). Namely, maintenance dialysis patients had higher risks of shock, ventricular arrhythmia or cardiac arrest, major bleeding events, and acute liver injury during the 14-days after admission to the intensive care unit (ICU) (4). Thus, in the latest reports, CKD emerged as the most common risk factor for severe COVID-19, preceded only by age ( 5, 6, 7).

The first evidence-based data on COVID-19 outcomes in patients treated with kidney replacement therapy from the ERACODA registry were published in the Nephrology Dialysis Transplantation journal in November 2020 (8). They showed a markedly higher 28-day COVID-19-related probability of death in kidney transplant (21.3%) and dialysis patients (25%) than what was observed in other populations. The numbers were even higher for hospitalized transplant and dialysis patients (23.6% and 33.5% respectively). Interestingly, an inverse incidence was observed related to the 28-day ICU admission rate showing a higher proportion of transplant than of dialysis patients admitted to ICU and treated with invasive ventilation (21% versus 12% respectively ). Mortality was primarily associated with advanced age in both groups, and also with frailty in dialysis patients (8). Nevertheless, when adjusted for age, sex, frailty, and classical risk factors for COVID-19 death (such as obesity, hypertension, diabetes, heart failure, chronic obstructive pulmonary disease, and smoking) the transplant patients had a higher mortality risk than the dialyzed ones (work in progress). Furthermore, dialyzed patients seem to more often have the asymptomatic disease compared to transplanted patients.

Although several therapeutic strategies have been evaluated for the treatment of COVID-19, no antiviral agents have yet been shown to be efficacious (9). The additional barrier for CKD patients is the fact that this population is often excluded from clinical trials, even though it is at higher risk for COVID-19-related mortality (10). Dexamethasone was found to reduce 28-day mortality in patients requiring invasive mechanical ventilation but showed no benefit in patients who did not require oxygen (13, 11). Unfortunately, there is currently no official recommendation on how to dose this drug in patients who already are on chronic corticosteroid treatment due to kidney transplants or other immune-related kidney diseases. A broad-spectrum antiviral medication Remdesivir was early identified as a promising therapeutic option for COVID-19 because of its ability to inhibit SARS-CoV-2 in vitro. It was superior to placebo in shortening the time to recovery in adults hospitalized with COVID-19 lower respiratory tract infection (9). Nevertheless, these investigations did not include patients with advanced CKD and GFR below 30 mL/min/1.73m2 related to the presumed safety issues due to carrier-related tubular toxicity for this drug (12).

The introduction of COVID-19 vaccines intended to provide acquired immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has raised several questions related to patients with CKD. In this population vaccines are often less efficient due to uremia and the use of immunosuppressive agents, especially in later stage CKD or patients on renal replacement therapy. Thus, various strategies have been investigated to improve immunization efficacy in these patients, such as changing the injection mode, adding repeat doses, use of adjuvants and immunostimulants to improve the immunogenicity of existing recombinant vaccines, and introducing the mammalian-cell derived vaccines (13). Unfortunately, the majority of the initial COVID-19 vaccination trials did not include patients with advanced CKD and on renal replacement therapy, thus the efficacy of the vaccines in this population remains elusive (14, 15).

Risk factors for COVID-19 mortality in the CKD population. Are they different from the general population?
Comprehensive global data analysis for COVID-19 mortality risk factors is still lacking, but numerous investigations are currently aiming to assess the predictors of death from this disease. One of the largest European studies on this topic evaluating risk factors in the general population was based on the data obtained from OpenSAFELY, an analytics platform that allowed analysis of pseudonymized primary care patient records from approximately 40% of the English population (6). According to this investigation, male sex, greater age, severe obesity, diabetes, severe asthma, and chronic heart disease were significantly associated with a greater risk of COVID-19 mortality in the general population (6).

Patients with CKD do not seem to have a higher risk of contracting COVID-19 compared to the general population. Nevertheless, once infected they are more likely to develop a severe form of the disease. The recently published data from the ERACODA registry gave an important insight into the risk factors for the fatal outcome of COVID-19 infection in this particularly vulnerable population (8). It presented data on the COVID-19-related outcomes for 768 dialysis and 305 kidney transplant patients registered between February 1 and May 1, 2020. The mortality rate from COVID-19 in dialysis patients ranged from 5% in non-hospitalized individuals to 34% among hospitalized patients, to 53% among patients requiring intensive care. Transplanted patients showed somewhat lower death rates – 3% for non-hospitalized patients, 24% for the hospitalized ones, and 45% for those treated in ICUs. In contrast to the general population, sex, diabetes, chronic heart, cardiovascular and respiratory disease were not associated with higher mortality in hemodialyzed patients. The only significant predictors of COVID-19- related mortality in this population were age, frailty, and severe obesity. Greater age was also the single statistically significant risk factor for mortality in the transplanted patients (8).

Another recently published study also presented results for the European population of patients on kidney replacement therapy based on the data obtained from the ERA-EDTA Registry from February 1 to April 30, 2020. It analyzed evidence for 3,285 dialyzed and 1,013 transplanted patients, mostly originating from France and Spain (16). The mortality rate from COVID-19 in both groups in this study was around 20%. Higher age was significantly associated with mortality in dialyzed patients with COVID-19, however, male sex was also a significant factor, which is in contrast to the results from the ERACODA registry (8, 16). This discrepancy can be explained by the difference in adjustment in multivariate models and adjusting only for age, without considering the effect of frailty or comorbidity, would return the same hazard ratios for both databases.

References

1. Noordzij M, Duivenvoorden R, Pena MJ, de Vries H, Kieneker LM; collaborative ERACODA authors. ERACODA: the European database collecting clinical information of patients on kidney replacement therapy with COVID-19. Nephrol Dial Transplant. 2020;35(12):2023-2025. doi: 10.1093/ndt/gfaa179.

2. Ko JY, Danielson ML, Town M; COVID-NET Surveillance Team. Risk Factors for COVID-19-associated hospitalization: COVID-19-Associated Hospitalization Surveillance Network and Behavioral Risk Factor Surveillance System. Clin Infect Dis. 2020:ciaa1419. doi: 10.1093/cid/ciaa1419.

3. Holman N, Knighton P, Kar Pet al. Risk factors for COVID-19-related mortality in people with type 1 and type 2 diabetes in England: a population-based cohort study. Lancet Diabetes Endocrinol. 2020;8(10):823-833. doi: 10.1016/S2213-8587(20)30271-0

4. Flythe JE, Assimon MM, Tugman M; STOP-COVID Investigators. Characteristics and Outcomes of Individuals With Pre-existing Kidney Disease and COVID-19 Admitted to Intensive Care Units in the United States. Am J Kidney Dis. 2021;77(2):190-203.e1. DOI: 10.1053/j.ajkd.2020.09.003

5. ERA-EDTA Council, ERACODA Working Group, Chronic kidney disease is a key risk factor for severe COVID-19: a call to action by the ERA-EDTA, Nephrology Dialysis Transplantation 2021; 36(1): 87–94. DOI: 10.1093/ndt/gfaa314

6. Williamson EJ, Walker AJ, Bhaskaran K, et al. Factors associated with COVID-19-related death using OpenSAFELY. Nature. 2020;584(7821):430-436. doi: 10.1038/s41586-020-2521-4.

7. Clark A, Jit M, Warren-Gash C; Centre for the Mathematical Modelling of Infectious Diseases COVID-19 working group. Global, regional, and national estimates of the population at increased risk of severe COVID-19 due to underlying health conditions in 2020: a modelling study. Lancet Glob Health. 2020;8(8):e1003-e1017. doi: 10.1016/S2214-109X(20)30264-3.

8. Hilbrands LB, Duivenvoorden R, Vart P; ERACODA Collaborators. COVID-19-related mortality in kidney transplant and dialysis patients: results of the ERACODA collaboration. Nephrol Dial Transplant. 2020;35(11):1973-1983. doi: 10.1093/ndt/gfaa261.

9. Beigel JH, Tomashek KM, Dodd LE,; ACTT-1 Study Group Members. Remdesivir for the Treatment of Covid-19 – Final Report. N Engl J Med. 2020;383(19):1813-1826. doi: 10.1056/NEJMoa2007764.

10. Major R, Selvaskandan H, Makkeyah YM, Hull K, Kuverji A, Graham-Brown M. The Exclusion of Patients with CKD in Prospectively Registered Interventional Trials for COVID-19-a Rapid Review of International Registry Data. J Am Soc Nephrol. 2020;31(10):2250-2252. doi: 10.1681/ASN.2020060877.

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. Adamsick ML, Gandhi RG, Bidell MR, et al. Remdesivir in Patients with Acute or Chronic Kidney Disease and COVID-19. J Am Soc Nephrol. 2020;31(7):1384-1386. doi: 10.1681/ASN.2020050589.

13. Reddy S, Chitturi C, Yee J. Vaccination in Chronic Kidney Disease. Adv Chronic Kidney Dis. 2019;26(1):72-78. doi: 10.1053/j.ackd.2018.10.002.

14. www.clinicaltrials.gov accessed November 11, 2020.

15. WHO The COVID-19 candidate vaccine landscape and tracker. Available at https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines accessed November 11, 2020.

16. Jager KJ, Kramer A, Chesnaye NC, et al. Results from the ERA-EDTA Registry indicate a high mortality due to COVID-19 in dialysis patients and kidney transplant recipients across Europe. Kidney Int. 2020;98(6):1540-1548. doi: 10.1016/j.kint.2020.09.006.

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