Clinical Kidney Journal, 2021, vol. 14, Suppl 1, i1–i5 doi: 10.1093/ckj/sfab039 Editorial Comment Clinical Kidney Journal EDITORIAL COMMENT COVID-19 and its impact on the kidney and the nephrology community Marı́a José Soler1 and Daniel Batlle2 1 Hospital Universitari Vall d’Hebron, Autonomous University of Barcelona, Barcelona, Spain and 2Department of Medicine, Division of Nephrology and Hypertension, Northwestern University Feinberg School of Medicine, Chicago, IL, USA Correspondence to: Marı́a José Soler; E-mail: mjsoler01@gmail.com; Daniel Batlle; E-mail: d-batlle@northwestern.edu The severe acute respiratory syndrome coronavirus 2 (SARS-CoV- term outcomes of COVID-19-related kidney disease in terms of 2), the coronavirus that causes the infection known as coronavirus recovery of kidney function or persistence of proteinuria, which disease 2019 (COVID-19), has spread rapidly causing a pandemic could add additional need for nephrology care. Taking all of this that has not only seriously affected human health, but also re- into consideration, the impact of COVID-19 in the nephrology stricted daily life activities and weakened the world economy to community and our patients could be potentially devastating. unprecedented levels. Most people who are COVID-19-positive for- An analysis of over 17 million adults found almost 11 000 tunately present with mild symptoms, but older people and those COVID-19-related deaths [3]. Advanced chronic kidney disease with comorbidities may present with severe respiratory complica- (CKD) was identified as one of the most important risk factors tions, often requiring care in intensive medical units. As of the for death in COVID-19 patients in this order: dialysis patients end of January 2021, mortality worldwide attributable to COVID-19 [adjusted Hazard Ratio (aHR) 3.69], transplant recipients (aHR has been estimated at 2 150 000. The death rate per 100 000 popu- 3.53) and CKD (estimated glomerular filtration rate <30 mL/min/ lation as reported by the John Hopkins Coronavirus Resource 1.73 m2) (aHR 2.52) [4]. The COVID-19 mortality risk in CKD Centre is depicted in Figure 1. The impact of COVID-19 on the ne- patients is actually greater than the risk observed in people phrology community has been important at different levels: (i) with diabetes and chronic heart disease, suggesting priority for patients with end-stage kidney disease on dialysis and those with clinical trials, vaccinations and future action plans in our ne- kidney transplants are at risk for COVID-19 complications and the phrology field [4]. Results from the European Renal Association mortality is high; (ii) acute kidney injury (AKI) ascribed to COVID- COVID-19 Database (ERACODA) revealed a 28-day mortality in 19 is a frequent complication of severe cases and moreover is as- kidney transplant and dialysis patients with COVID-19 as high sociated with high mortality; and (iii) there is COVID-19-related as 21.3 and 25%, respectively [5]. Hypertension, diabetes melli- glomerular involvement, characterized in some cases by collaps- tus, coronary artery disease, heart failure and chronic lung dis- ing glomerulopathy and tubular damage in other cases. ease were not identified as independent risk factors [6]. In All of this COVID-19-related kidney pathology adds greatly concordance with these results, a study from Dialysis Clinic to the already high global burden of kidney disease in terms of Inc., a national not-for-profit dialysis provider caring for >15 000 human suffering and costs to the medical systems. It is esti- maintenance dialysis patients at 260 outpatient dialysis clinics, mated that the number of people that suffer from kidney dis- showed that dialysis patients are at high risk of developing ease in the world exceeds 850 million, which is twice the COVID-19, and 90-day mortality ascribed to COVID-19 estimated number of people with diabetes (422 million). This approaches 25% [7]. Among dialysis patients, residence in a places kidney disease among one of the most common of all long-term care facility, Black race, male sex, diabetes, receipt of diseases around the world [1]. In-hospital patients seen by in-centre dialysis and treatment at an urban dialysis centre nephrologists, moreover, are the more complex, with the high- were identified as risk factors for COVID-19 infection. In dialysis est morbidity and mortality [2]. We do not know yet the long- patients with COVID-19 disease, older age, hypertension, Received: 28.1.2021; Editorial decision: 28.1.2021 C The Author(s) 2021. Published by Oxford University Press on behalf of ERA-EDTA. V This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com i1 i2 | M.J. Soler and D. Batlle FIGURE 1: COVID-19 deaths per 100 000 population. Extracted from John Hopkins Coronavirus Resource Center (date: 25 January 2021). FIGURE 2: Targeting of ACE2 by SARS-CoV-2 may result in Ang dysregulation, innate and adaptive immune pathway activation and hypercoagulation to result in organ injury and AKI associated with COVID-19. Organ crosstalk between the injured lungs, the heart and the kidney may further propagate injury. CD8þ T cells and natural killer cells can restrain macrophage activation and are potential targets for SARS-CoV-2. ATN, acute tubular necrosis; TMPRSS2, transmembrane protease, serine 2. From Batlle et al. J Am Soc Nephrol 2020; 31: 1380–1383 [16] (with permission). Editorial Comment | i3 congestive heart failure and peripheral vascular disease as well that require intensive care [11, 12]. In such patients, the inci- as wheelchair use, were associated with higher risk of death [7]. dence of AKI is very high and is associated with high mortality The nephrology community throughout the world has [13–15]. The pathophysiology of this form of AKI is not well un- responded well to the challenges posed by COVID-19 and the derstood, but several factors including activation of the innate high demand for kidney replacement therapies for patients immune system, complement activation, Angiotensin (Ang) II with AKI and those already on dialysis. overactivity and the development of a hypercoagulable state In this issue, Dr Cozollino et al. describe strategies employed have been incriminated (Figure 2) [16]. In many patients, how- to avoid COVID-19 infection in patients with end-stage kidney ever, AKI is simply attributable to hypotension and sepsis. disease and the important role of promoting home dialysis and Another entity that has been frequently described in patients peritoneal dialysis [8]. In situations of medical crisis, epidemio- with COVID-19 is collapsing glomerulopathy, usually associated logical studies for assessing mortality and outcomes in our dial- with AKI and in African Americans with APOL risk alleles [17– ysis and transplant programmes are of the upmost importance, 19]. as described by Dr Noordzij et al. Nephrologists have been Despite the intensity of medical care required to take care of mainly trained to take care of patients, and yet the interpreta- these sick patients with COVID-19 by the nephrology commu- tion of emerging new studies is of crucial importance for the nity, there has also been an effort to convey the new informa- progress of our specialty. Dr Noordzij et al. offer clues for inter- tion that has been rapidly accrued during the past year. In this preting epidemiological papers in the context of COVID-19 and issue of CKJ, Sharma et al. discuss AKI in COVID-19 patients, kidney disease. The authors bring up the need for awareness of reviewing the histopathological changes based on kidney biop- the differences in the study design, outcome definitions and ap- sies and autopsies [20]. Drs Mohamed and Velez discuss the im- plied methods that should help future and young investigators portance of proteinuria including the assessment and methods to better interpret and design epidemiological studies in the ne- for its detection, the mechanisms involved and the significance phrology field [9]. Dr Toapanta et al. discuss COVID-19 in kidney of ‘de novo’ proteinuria in COVID-19 patients [21]. transplants, a topic of great importance since mortality in kid- Ang-converting enzyme 2 (ACE2) is the main receptor for ney transplant recipients with COVID-19 infection has been es- SARS-CoV-2 viral cell entry [22, 23]. In the kidney, ACE2 is pre- timated to be as high as 20%. Of note, incidence of AKI and the sent mainly in the apical border of the proximal tubular cells need of renal replacement therapy in hospitalized kidney trans- and, to a lesser extent, in podocytes (Figure 3) [24]. It is still a plant patients with COVID-19 infection is high. Whereas in the matter of some debate whether kidney SARS-CoV-2 invasion general population, the variability of the reported AKI-related causes, in part, the manifestations of COVID-19 described COVID-19 infection is high and varies depending on the country above. There are a few studies that have documented well the and type of study, studies performed in kidney transplant presence of SARS-CoV-2 in the glomerulus and in proximal patients showed consistent results with an incidence of AKI tubular cells [25]. around 45%. The occurrence of AKI risk in this specific CKD pop- Following the recognition in January 2020 that ACE2 is the ulation is discussed by Toapanta et al. [10]. receptor for SARS-CoV-2, like SARS-CoV, concerns were raised The impact of COVID-19 disease affects not only patients that some drugs such as the renin–Ang system (RAS) blockers with pre-existing kidney disease or kidney transplantation. could be deleterious in COVID-19 patients [26]. The concern was De novo kidney disease is commonly seen in hospitalized based on studies prior to COVID-19, most of them in experimen- patients with COVID-19, particularly those with severe disease tal animals, showing that ACE2 could be upregulated in the FIGURE 3: A depiction of ACE2, the main receptor of SARS-CoV-2, in glomerular podocytes using immunogold labelling (left) and proximal tubular cells by immunofluo- rescence (right). GBM, glomerular basement membrane. Data modified from Ye et al. J Am Soc Nephrol 2006; 17: 3067–3075 [24]. i4 | M.J. Soler and D. Batlle heart, kidney vasculature and other organs [27, 28]. Recent work replacement therapy with COVID-19. Nephrol Dial Transplant has shown, however, that in the lungs, the site of SARS-CoV-2 2020; 35: 2023–2025 entry, ACE2 expression is not increased [29]. After the initial 7. Hsu CM, Weiner DE, Aweh G et al. COVID-19 Infection among US concern, several publications and position statements by scien- dialysis patients: risk factors and outcomes from a national di- tific specialty societies reassured the medical community that alysis provider. Am J Kidney Dis 2021; S0272-6386(21)00025-1. doi: there were no grounds to abandon these medications pending 10.1053/j.ajkd.2021.01.003. Online ahead of print studies addressing this issue [30–32]. In this issue, Cohen et al. 8. Cozzolino M, Conte F, Zappulo F et al. COVID-19 pandemic provide a critical review of the physiologic and epidemiologic era: is it time to promote home dialysis and peritoneal dialy- evidence of the interactions between RAS blockade and COVID- sis? Clin Kidney J 2021; 14 (Suppl 1): i6–i13 19 that, in our opinion, brings this ongoing discussion towards 9. Noordzij M, Vart P, Duivenvoorden R et al. Pitfalls when com- an end [33]. One year later, after all the concerns were raised paring COVID-19-related outcomes across studies—lessons and with multiple publications addressing this issue, it seems learnt from the ERACODA collaboration. Clin Kidney J 2021; 14 quite clear that the use of RAS blockers is generally safe in the (Suppl 1): i14–i20 context of COVID-19. 10. Toapanta N, Torres IB, Sellarés J et al. Kidney transplantation In summary, this issue of CKJ covers current knowledge of and COVID-19 renal and patient prognosis. Clin Kidney J 2021; COVID-19 disease and its impact on the kidney. It is hoped 14 (Suppl 1): i21–i29 that the various contributions will provide the nephrology 11. Cheng Y, Luo R, Wang K et al. Kidney disease is associated community with valuable information that is useful for the care with in-hospital death of patients with COVID-19. Kidney in- of patients with underlying kidney disease and those with the ternational 2020; 97: 829–838 pathologies that have emerged related to the COVID-19 12. Yang X, Yu Y, Xu J et al. Clinical course and outcomes of criti- pandemic. cally ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respirat Med 2020; 8: 475–481 FUNDING 13. Pei G, Zhang Z, Peng J et al. Renal involvement and early This article is part of a supplement supported by Fresenius prognosis in patients with COVID-19 pneumonia. J Am Soc Medical Care without any influence on its content. Nephrol 2020; 31: 1157–1165 14. Fisher M, Neugarten J, Bellin E et al. AKI in hospitalized patients with and without COVID-19: a comparison study. CONFLICT OF INTEREST STATEMENT J Am Soc Nephrol 2020; 31: 2145–2157 D. Batlle is coinventor of patents entitled ‘Active Low Molecular 15. Hirsch JS, Ng JH, Ross DW et al. Acute kidney injury in Weight Variants of Angiotensin Converting Enzyme 2’, ‘Active patients hospitalized with COVID-19. Kidney Int 2020; 98: low molecular weight variants of Angiotensin Converting 209–218 Enzyme 2 (ACE2) for the treatment of diseases and conditions of 16. Batlle D, Soler MJ, Sparks MA et al.; on behalf of the COVID-19 the eye’ and ‘Shorter soluble forms of Angiotensin Converting and ACE2 in Cardiovascular, Lung, and Kidney Working Enzyme 2 (ACE2) for treating and preventing coronavirus infec- Group. Acute kidney injury in COVID-19: emerging evidence tion.’ D. Batlle is founder of Angiotensin Therapeutics Inc. D. of a distinct pathophysiology. J Am Soc Nephrol 2020; 31: Batlle has received consulting fees from AstraZeneca, Relypsa, 1380–1383 and Tricida, all unrelated to this work. D. Batlle received unre- 17. Velez JCQ, Caza T, Larsen CP. COVAN is the new HIVAN: the lated support from a grant from AstraZeneca. M.J. Soler has no re-emergence of collapsing glomerulopathy with COVID-19. conflict of interest to declare related to this work. Nat Rev Nephrol 2020; 16: 565–567 18. Wu H, Larsen CP, Hernandez-Arroyo CF et al. AKI and col- lapsing glomerulopathy associated with COVID-19 and REFERENCES APOL1 high-risk genotype. J Am Soc Nephrol 2020; 31: 1. Jager KJ, Kovesdy C, Langham R et al. A single number for ad- 1688–1695 vocacy and communication—worldwide more than 850 mil- 19. Shetty AA, Tawhari I, Safar-Boueri L et al. COVID-19-associ- lion individuals have kidney diseases. Nephrol Dial Transplant ated glomerular disease. J Am Soc Nephrol 2021; 32: 33–40 2019; 34: 1803–1805 20. Sharma P, Ng JH, Bijol V et al. Pathology of COVID-19-associ- 2. Tonelli M, Wiebe N, Manns BJ et al. Comparison of the com- ated acute kidney injury. Clin Kidney J 2021; 14 (Suppl 1): plexity of patients seen by different medical subspecialists i30–i39 in a universal health care system. JAMA Netw Open 2018; 1: 21. Mohamed MMB, Velez JCQ. Proteinuria in COVID-19. Clin e184852-e Kidney J 2021; 14 (Suppl 1): i40–i47 3. Williamson EJ, Walker AJ, Bhaskaran K et al. Factors associ- 22. Shang J, Ye G, Shi K et al. Structural basis of receptor recogni- ated with COVID-19-related death using OpenSAFELY. tion by SARS-CoV-2. Nature 2020; 581: 221–224 Nature 2020; 584: 430–436 23. Davidson AM, Wysocki J, Batlle D. Interaction of SARS-CoV-2 4. ERA-EDTA Council, ERACODA Working Group. Chronic kidney and other coronavirus with ACE (angiotensin-converting disease is a key risk factor for severe COVID-19: a call to action enzyme)-2 as their main receptor: therapeutic implications. by the ERA-EDTA. Nephrol Dial Transplant 2021; 36: 87–94 Hypertension 2020; 76: 1339–1349 5. Hilbrands LB, Duivenvoorden R, Vart P et al. ERACODA 24. Ye M, Wysocki J, William J et al. Glomerular localization Collaborators. COVID-19-related mortality in kidney trans- and expression of Angiotensin-converting enzyme 2 and plant and dialysis patients: results of the ERACODA collabo- Angiotensin-converting enzyme: implications for albumin- ration. Nephrol Dial Transplant 2020; 35: 1973–1983 uria in diabetes. J Am Soc Nephrol 2006; 17: 3067–3075 6. Noordzij M, Duivenvoorden R, Pena MJ et al. collaborative 25. Puelles VG, Lütgehetmann M, Lindenmeyer MT et al. ERACODA authors. ERACODA: the European database col- Multiorgan and renal tropism of SARS-CoV-2. N Engl J Med lecting clinical information of patients on kidney 2020; 383: 590–592 Editorial Comment | i5 26. Fang L, Karakiulakis G, Roth M. Are patients with hyperten- 30. Danser AJ, Epstein M, Batlle D. Renin-angiotensin system sion and diabetes mellitus at increased risk for COVID-19 blockers and the COVID-19 pandemic: at present there is no infection? Lancet Respirat Med 2020; 8: e21 evidence to abandon renin-angiotensin system blockers. 27. Ferrario CM, Jessup J, Chappell MC et al. Effect of Hypertension 2020; 75: 1382–1385 angiotensin-converting enzyme inhibition and angiotensin 31. Sparks MA, South A, Welling P et al. Sound science before II receptor blockers on cardiac angiotensin-converting en- quick judgement regarding RAS blockade in COVID-19. Clin J zyme 2. Circulation 2005; 111: 2605–2610 Am Soc Nephrol 2020; 15: 714–716 28. Soler MJ, Ye M, Wysocki J et al. Localization of ACE2 in the 32. Vaduganathan M, Vardeny O, Michel T et al. Renin–angioten- renal vasculature: amplification by angiotensin II type 1 sin–aldosterone system inhibitors in patients with Covid-19. receptor blockade using telmisartan. Am J Physiol Renal N Engl J Med 2020; 382: 1653–1659 Physiol 2009; 296: F398–F405 33. Cohen JB, South AM, Shaltout HA et al. Renin–angiotensin 29. Wysocki J, Lores E, Ye M et al. Kidney and lung ACE2 expression system blockade in the COVID-19 pandemic. Clin Kidney J after an ACE inhibitor or an Ang II receptor blocker: implications 2021; 14 (Suppl 1): i48–i59 for COVID-19. J Am Soc Nephrol 2020; 31: 1941–1943