PRESENTED BY
ANNETTE BRUCHFELD

Presentation Summary

Written by Jasna Trbojevic-Stankovic
Reviewed by Annette Bruchfeld

Coronavirus disease 2019 (COVID-19) is a highly contagious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, primarily manifesting as an acute respiratory illness with interstitial and alveolar pneumonia. It emerged as an epidemic in China, but spread worldwide within months, prompting the World Health Organization to declare a global pandemic in March 2020. According to the latest reports most patients with new COVID-19 have mild to moderate clinical signs of infection, presenting with a flu-like illness. Still, about 20% of cases have severe disease, with dyspnoea, respiratory or circulatory issues, or critical condition, with respiratory failure, septic shock and/or multiple organ failure (1). The fundamental goals of the global interventions so far have been to lower and delay the epidemic peak in order to slow the spread of the disease and reduce the burden on health care facilities (Figure 1).

Figure 1. The presumed course of the COVID-19 epidemic with and without proactive measures (2)

 

There are several publications undergoing peer reviews discussing chronic kidney disease (CKD) as a risk factor for the severe form of COVID-19. A yet unpublished meta-analysis by Zhao et al. identifies CKD patients as those with the highest risk of developing the severe form of COVID-19, followed by patients with chronic obstructive pulmonary disease and those with cerebrovascular disease. Age above 50 years, male sex and smoking habit have also been identified as significant predictors of disease severity in this study (3).

Previous coronavirus infections, SARS and the Middle East respiratory syndrome (MERS), were associated with acute kidney injury (AKI) in 5 to 15% of the cases, and carried a high mortality rate (4). Cheng et al. recently reported that amongst 701 consecutive hospitalized COVID-19 adult patients 5.1% developed AKI, while proteinuria and haematuria on admission were present in 43.8% and 26.7% of the patients respectively which were associated with in-hospital deaths in more severe forms (5). A recent pre-print study from the US has reported the incidence of AKI to be 46 % (6)

The mechanism of kidney involvement as a target organ in COVID-19 is still not clear. The organ can suffer as a consequence of multiorgan failure and shock, the cytokine storm or from direct infection, which has been observed in tubular cells and podocytes. SARS-CoV-2 binds to angiotensin-converting enzyme 2 (ACE2) receptors, which are abundant in podocytes and proximal tubular epithelial cells, to enter the cells, as shown in a study by study by Xu et al(7). Postmortem histological analysis of kidney tissue has demonstrated severe acute tubular necrosis, lymphocyte and CD68+ macrophages tubulointerstitial infiltration, accumulation of the virus antigen and enhanced complement C5b-9 deposition in the tubules (8).

The mainstay of the therapeutic interventions for renal involvement in COVID-19 patients so far have been general and supportive care. Other interventions include strategies to reduce the uptake of the virus in cells, direct antiviral action (as suggested by hydrochloroquine in vitro), use of convalescent plasma with antiviral antibodies, immunomodulating drugs to prevent and treat cytokine storm and induction of innate immunity. Mostly repurposed drugs and very few new drugs have been used in the treatment of these patients. Also, not many randomized control trials have been published so far to give any definite conclusions on the efficacy of specific therapeutic interventions. There are several hundred ongoing clinical trials for COVID-19 treatment that will probably contribute more to our knowledge of the optimum treatment of this disease.

Notably, there have been no randomized control studies involving CKD patients with COVID-19. The dose of hydroxychloroquine, which has been used with some potential benefit in certain cases, notably in Spanish registry data (9). Dosage should however be reduced in patients with a glomerular filtration rate (GFR) under 30 ml/min, and caution should be applied when combined with other drugs due to possible interactions. The efficacy and safety of its combination with azithromycin in the treatment of SARS-CoV2 infection are unknown and yet to be confirmed. Remdesivir, which has succesfully been used in the treatment of ebola and is under investigation in COVID 19, is contraindicated in patients with GFR<30ml/min. The IL6 inhibitor, tocilizumab, has been successfully used in the treatment of rheumatoid arthritis and vasculitis, but there is little data on its application in dialysis patients. In general and perhaps also in this population, tocilizumab is usually given as a single dose to treat the severe cytokine storm which is associated with adverse outcome. As hyperinflammation in combination with hypercoagulability and thromboembolic events are recognized as markers of critical disease the use of high doses of anticoagulation therapy are increasingly used but also steroids. Other therapies include the need for continuous renal replacement therapy in AKI and the potential use of CytoSorb filters currently in clinical trials for patients with cytokine storm.

Advice from the ERA-EDTA Immunonephrology Working Group
The current opinion-based advice from the ERA-EDTA Immunonephrology Working Group for CKD patients with glomerulonephritis or vasculitis is to continue with immunosuppression in asymptomatic COVID-19, and reduce it cautiously, balancing the risk of relapse, in symptomatic patients. New onset or relapsing vasculitis should be treated with immunosuppressive drugs, but for new-onset glomerulonephritis supportive care may be recommended during the near future, unless it presents with a severe nephrotic syndrome or a substantial rise in creatinine. Rituximab as maintenance therapy should be postponed if clinically possible, and kidney biopsies should be performed on a priority basis (10).
Immunosuppressive therapy should be continued in asymptomatic kidney transplant patients, but antiretroviral Kaletra should be avoided due to challenging drug interactions. Transplanted patients with severe COVID-19 should be treated conjointly with intensivists and infectious medicine specialists. A possible therapeutic concept and potential timelines for COVID-19 patients is presented in Figure 2.

Figure 2. The timeline of interventions in COVID-19 patients

References

1. Report of the WHO-China joint mission on coronavirus disease (COVID-19). Available at: https://www.who.int/docs/default-source/coronaviruse/who-china-joint-mission-on-covid-19-final-report.pdf. Accessed April 28, 2020.

2. Bruchfeld A. COVID-19 infection – some implications for nephrology. Available at: https://www.era-edta.org/en/education/era-edta-webinars/ Accessed April 28, 2020.

3. Xianxian Zhao, Bili Zhang, Pan Li, Chaoqun Ma, Jiawei Gu, Pan Hou, Zhifu Guo, Hong Wu, Yuan Bai. Incidence, clinical characteristics and prognostic factor of patients with COVID-19: a systematic review and meta-analysis. medRxiv 2020.03.17.20037572; doi: https://doi.org/10.1101/2020.03.17.20037572

4. Naicker S, Yang C-W, Hwang S-J, Liu B-C, Chen J-H, Jha V. The Novel Coronavirus 2019 epidemic and the kidneys. Kidney Int 2020;97(5):824-828.

5. Cheng Y, Luo R, Wang K, et al. Kidney disease is associated with in-hospital death of patients with COVID-19. Kidney Int 2020;97(5):829-838.

6. Lili Chan, Kumardeep Chaudhary, Aparna Saha, et al. . Acute Kidney Injury in Hospitalized Patients with COVID-19
medRxiv 2020.05.04.20090944; doi: https://doi.org/10.1101/2020.05.04.20090944

7. Pan, X., Xu, D., Zhang, H. et al. Identification of a potential mechanism of acute kidney injury during the COVID-19 outbreak: a study based on single-cell transcriptome analysis. Intensive Care Med (2020). https://doi.org/10.1007/s00134-020-06026-1

8. Diao B, Wang C, Wang R, et al. Human kidney is a target for novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Preprint. Available at: https://www.medrxiv.org/content/10.1101/2020.03.04.20031120v4 Accessed April 28, 2020.

10. COVID-19 News and information for the ERA-EDTA Community and kidney patients https://www.era-edta.org/en/covid-19-news-and-information/#toggle-id-8

NDT-E Summary Articles