Clinical Kidney Journal, 2020, vol. 13, no. 3, 297–306 doi: 10.1093/ckj/sfaa104 CKJ Review CKJ R EV IEW Coronavirus disease 2019 in chronic kidney disease Luis D’Marco1, Marı́a Jesús Puchades1, Marı́a Romero-Parra1, Elena Gimenez-Civera1, Marı́a José Soler 2, Alberto Ortiz3 and José Luis Gorriz 1,* 1 Nephrology Department, Hospital Clı́nico Universitario, INCLIVA, Universidad de Valencia, Valencia, Spain, 2 Nephrology Department, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain and 3IIS-Fundación Jiménez Diaz UAM and School of Medicine, Universidad Autonoma de Madrid, Madrid, Spain 1 Correspondence to: José Luis Gorriz; E-mail: jlgorriz@senefro.org; Twitter handle:@PepaSolerR ABSTRACT The clinical spectrum of coronavirus disease 2019 (COVID-19) infection ranges from asymptomatic infection to severe pneumonia with respiratory failure and even death. More severe cases with higher mortality have been reported in older patients and in those with chronic illness such as hypertension, diabetes or cardiovascular diseases. In this regard, patients with chronic kidney disease (CKD) have a higher rate of all-type infections and cardiovascular disease than the general population. A markedly altered immune system and immunosuppressed state may predispose CKD patients to infectious complications. Likewise, they have a state of chronic systemic inflammation that may increase their morbidity and mortality. In this review we discuss the chronic immunologic changes observed in CKD patients, the risk of COVID-19 infections and the clinical implications for and specific COVID-19 therapy in CKD patients. Indeed, the risk for severe COVID-19 is 3-fold higher in CKD than in non-CKD patients; CKD is 12-fold more frequent in intensive care unit than in non-hospitalized COVID-19 patients, and this ratio is higher than for diabetes or cardiovascular disease; and acute COVID- 19 mortality is 15–25% for haemodialysis patients even when not developing pneumonia. Keywords: cardiovascular disease, chronic kidney disease, COVID-19, immunity, SARS-CoV-2, therapy INTRODUCTION disease was termed coronavirus disease 2019 (COVID-19) by the World Health Organization [2]. Since the first reports of some cases of atypical pneumonia Coronaviruses were described for the first time in 1966 by in China in December 2019 and the extreme measures Tyrell and Bynoe, who cultivated the viruses from patients with adopted by the Chinese government in closing the city of common colds [3]. They are enveloped, positive, single-stranded Wuhan (the focus of the problem), everything rapidly large RNA viruses that not only infect humans, but also a wide changed. The causative agent of this respiratory disease was range of animals (bats, pangolins, cats, pigs and birds, among identified as a novel coronavirus [1], called severe acute re- others). The genome size varies between 26 and 32 kb. Based on spiratory syndrome coronavirus 2 (SARS-CoV-2), and the their morphology as spherical virions with a core shell and Received: 12.4.2020; Editorial decision: 6.5.2020 C The Author(s) 2020. 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 297 298 | L. D’Marco et al. Table 1. COVID-19 in the CKD population Key points: the COVID-19 pandemic and the CKD population Decreased kidney function causes marked alterations in the immune system. CKD patients are prone to develop all-cause infections. CKD represents a risk factor for COVID-19 complications. Causal conditions for CKD (hypertension, DM and CVD) are risk factors for COVID-19 mortality. Special measures must be taken in CKD Stage 5 on dialysis and renal transplant patients. surface projections resembling a solar corona, they were termed antiviral IFN type I effect, resulting in uncontrolled viral replica- coronaviruses. At present, four subfamilies are recognized: a-, tion, with the consequent influx of neutrophils and monocytes/ b-, c- and d-coronaviruses [4]. SARS-CoV-2 belongs to the B line- macrophages and hyperproduction of pro-inflammatory cyto- age of b-coronaviruses and is closely related to the SARS-CoV. kines, the so-called cytokine storm. Thus oxidative stress and The major four structural genes encode the nucleocapsid pro- inflammation are crucial for defence against COVID-19 infec- tein (N), the spike protein (S), a small membrane protein (SM) tion, but they may be deleterious if not properly regulated [14]. and the membrane glycoprotein (M), with an additional mem- Specific lymphocyte T helper (Th1/Th17) activation may inten- brane glycoprotein (HE) occurring in the HCoV-OC43 and HKU1 sify inflammatory responses. Severe COVID-19 is characterized b-coronaviruses [5]. by severe lymphopaenia that is associated with an increased The clinical spectrum of COVID-19 infection is very variable, risk of death [15]. The high mortality of patients with severe ranging from asymptomatic infection, anosmia, ageusia or mi- lymphopaenia may reflect resistance to currently available ex- nor upper respiratory tract illness to severe pneumonia with re- perimental therapies. Lymphocyte depletion is thought to im- spiratory failure and even death [6]. Diarrhoea and cutaneous pair antiviral defences and there have been attempts, discussed and thrombotic manifestations were recently described [7, 8]. below, at boosting these defences. Natural killer (NK) cells are More severe cases with higher rates of mortality have been essential for defence against virus infections in general, and as reported in older patients and in those with chronic illness such discussed below, some cell-based therapeutic approaches aim as cardiovascular disease, hypertension or diabetes. However, at increasing their efficacy. They are thought to be activated in deaths have also occurred in previously healthy young patients. COVID-19 and may contribute to both viral clearance and tissue Patients with chronic kidney disease (CKD) are expected to be at injury. Indeed, there is profound depletion of NK cells [16]. higher risk of severe disease since their rate of all-type infec- There is little information on T regulatory cells (Tregs) and tions and the prevalence of cardiovascular disease are higher COVID-19. In one report, patients with COVID-19 had lower than in the general population. Marked alterations in the im- numbers of Tregs, and this was more obvious in severe cases mune system have been reported in CKD patients, leading to an [15]. Regarding a potential role of Tregs in disease pathogenesis, immunosuppressed state and frequent infectious complica- there is information from other coronavirus infections. Thus, in tions. Likewise, chronic systemic inflammation may also con- murine models of central nervous system infection, Tregs lim- tribute to higher morbidity and mortality in CKD patients [9]. In ited T cell–mediated tissue damage without impairing viral this review we discuss the pathogenesis of COVID-19, the clearance [17]. Meanwhile, B and plasma cells produce specific chronic immunologic changes observed in CKD patients and the antibodies that may help neutralize SARS-CoV-2. Both uncon- risk of COVID-19 and the clinical implications for CKD patients trolled viral replication and the cytokine storm are thought to (Table 1). contribute to disease pathogenesis, as illustrated by therapeutic trials of both antiviral drugs and tocilizumab [neutralizing anti- interleukin-6 (IL-6) antibody; NCT04317092]. COVID-19 PATHOGENESIS Additionally, the findings of endothelial cell injury and For most patients, COVID-19 will affect mainly the upper and thrombotic microangiopathy have raised the spectrum of com- lower respiratory tract. The primary mode of infection is plement involvement and triggered the use of anticomplement human-to-human transmission through close contact, which strategies [18, 19]. In case reports, both the anticomplement C5 occurs via spraying droplets from an infected individual antibody eculizumab [20] and the complement C3 inhibitor through coughing or sneezing. Additionally, surfaces are AMY-101 (Amyndas Pharmaceuticals, Philadelphia, PA, USA) thought to retain the virus for variable periods of time, depend- [21] were apparently effective in COVID-19 and an eculizumab ing on their nature [10]. COVID-19 has an asymptomatic incuba- clinical trial is ongoing (NCT04288713). tion period of 2–14 days during which the virus can be At present, the mortality rate of COVID-19 worldwide is transmitted [11]. 2.4% of diagnosed cases. SARS-CoV-2 infection causes both After entering the lungs, COVID-19 infects cells expressing pulmonary and systemic severe inflammation, leading to multi- certain cell surface receptors such as angiotensin-converting organ dysfunction. Acute respiratory distress syndrome and re- enzyme 2 (ACE2; e.g. alveolar type 2 cells) or CD147 [also known spiratory failure, sepsis and heart failure and thrombotic as basigin, extracellular matrix metalloproteinase inducer complications have been reported as the most common causes (EMMPRIN) and leukocyte activation antigen M6], which besides of death [22]. Mortality is higher in elderly people and those lung cells, is also expressed in kidney tubular cells, among with underlying health conditions such as hypertension, cardio- others [11, 12] (https://www.proteinatlas.org/ENSG00000172270- vascular disease and diabetes [23]. The case fatality rate during BSG/tissue). In healthy individuals, the innate immune re- the first week of the epidemic was 0.15% [95% confidence inter- sponse against viral infection relies heavily on interferon (IFN) val (CI) 0.12–0.18)] in mainland China, excluding the city of type I responses and its downstream cascade that culminates in Wuhan, in which this estimation was 5.25% (95% CI 4.98–5.51) controlling viral replication and induction of effective adaptive [24]. Outside China, the USA, Italy and Spain have the highest immune response [13]. Coronaviruses may dampen the mortality rates. The mortality rate will depend on testing COVID-19 in chronic kidney disease | 299 policies (it will be higher when just severely ill patients that are 72% of these patients presented with no obvious symptoms. hospitalized are tested) as well as on the overwhelming of This could mask the suspicion of active disease and transform healthcare facilities [mortality shoots up once hospitals run out them into carriers and transmitters of the virus. During a short of ventilators or intensive care unit (ICU) beds]. follow-up (<2 months), 6/37 (16%) COVID-19 HD patients and 1/ In a retrospective, multicentre Chinese cohort study, older 193 (0.5%) COVID-19-free HD patents died. The high mortality age, D-dimer levels >1 lg/mL and higher Sequential Organ was not related to respiratory causes, which would be in line Failure Assessment scores on admission were associated with with the current understanding of the pathogenesis of lung in- higher odds of in-hospital death [6]. Furthermore, elevated se- jury (mainly inflammation mediated) and the low evidence of rum levels of IL-6, high-sensitivity cardiac troponin I, lactate de- inflammation observed. How to explain the high mortality hydrogenase and lymphopaenia were more commonly seen in then? This is not surprising either, given that viral (e.g. influ- severe COVID-19-affected patients. The age-dependent defects enza) or severe infection is associated with an increased risk of in T and B cell function and the excess production of type 2 cardiovascular events both in the general population and in cytokines could lead to a deficiency in the control of viral repli- CKD patients [32, 33]. The Wuhan report is in line with prelimi- cation and/or more prolonged and intense pro-inflammatory nary data from the national registry of COVID-19 from the responses, potentially leading to poor outcome [6]. In another Spanish Society of Nephrology that includes 637 patients to small study of 68 hospitalized patients, the risk of death was date (409 patients on HD, 203 transplanted patients and 25 higher in patients with cardiovascular disease. Older age, the patients on peritoneal dialysis) and shows a mortality rate of presence of underlying diseases, secondary infections and ele- 21% (https://mailchi.mp/senefro/registro-epidemiolgico-vhc- vated serum inflammatory cytokines were associated with in- vhb-vih-1314521; date last accessed 8 April 2020). creased mortality. They suggested that COVID-19 mortality might be due to virus-activated ‘cytokine storm syndrome’ or fulminant myocarditis [25]. Further reports have linked cardio- KIDNEY INVOLVEMENT IN COVID-19 vascular disease with a higher risk of mortality [26]. Higher body mass index is more often seen in critical patients and non- Beyond respiratory cells, other organs might be affected by survivors. Aggravating factors include fulminant inflammation, SARS-CoV-2, including the kidneys, ileum and heart, especially lactic acid accumulation and thrombotic events [26]. High ferri- in the presence of viraemia. Thus cultured renal proximal tubu- tin has recently emerged as a severe disease indicator [27]. lar epithelial cells, glomerular mesangial cells and podocytes express ACE2 on their surface and may represent another target for COVID-19 [34]. Additionally, CD147 is expressed in the baso- CKD AND COVID-19 lateral membrane of proximal and distal tubular cells (https:// At present, the literature regarding CKD and COVID-19 is scarce. www.proteinatlas.org/ENSG00000172270-BSG/tissue; Figure 2A). A PubMed search for ‘(CKD OR chronic kidney disease) and (COVID-19 OR SARS-CoV-2)’ performed on 10 April 2020 dis- A closed only one relevant citation, corresponding to a letter to 14 12 the editor meta-analysis that recorded a higher risk of severe 12 COVID-19 disease in CKD patients [odds ratio 3.03 (95% CI 1.09– 10 9 % with CKD 8.47), I2 ¼ 0.0%, Cochran’s Q, P ¼ 0.84] after analysing four studies 8 including 1389 COVID-19 patients, among which 273 (19.7%) had severe disease [28]. An analysis of 7162 laboratory-confirmed 6 COVID-19 cases in the USA confirmed that CKD was 12-fold 4 more frequent in those with ICU admission and 9-fold more fre- 2 1 quent in hospitalized, non-ICU COVID-19 patients than in those 0 not hospitalized. The increased prevalence of CKD in ICU ad- ICU admission Hospitalized, non-ICU Not hospitalized mission was higher than the prevalence of other pre-existing B conditions (ratio of prevalence in ICU versus not hospitalized ICU versus non-hospitalized paents Fold difference in prevalence in 14 patients ranged from 2- to 6.7-fold; Figure 1A and B), although 12 these data were not adjusted for covariates [29]. In an ‘in press’ 10 report, evidence of kidney disease at admission in 701 patients 8 hospitalized for COVID-19 was associated with a significantly 6 higher risk for in-hospital death in an adjusted analysis. This 4 ranged from 1.8-fold for proteinuria to 2.1-fold for elevated se- 2 rum creatinine and 3-fold for haematuria. The risk associated 0 with acute kidney injury (AKI) ranged from 1.9- to 4.4-fold higher depending on AKI severity [30]. However, the study de- sign could not distinguish between pre-existent CKD and COVID-19-associated kidney injury. Hence CKD patients should be included in the COVID-19 high-risk groups. Additionally, the main causes of CKD are cardiovascular, hypertension and/or di- FIGURE 1: (A) Prevalence of CKD according to severity of COVID-19. There is a abetes related. In this regard, a preprint report, not yet peer- gradient in CKD prevalence from the more severe (ICU patients) to the less se- reviewed, of a small study of 37 COVID-19 haemodialysis (HD) vere patients (not hospitalized). (B) Prevalence of CKD and additional pre-exist- ing conditions according to COVID-19 severity. The ratio of the prevalence in patients from Wuhan observed lower peripheral blood T cells, ICU patients versus the prevalence in non-hospitalized patients is presented. Th cells, killer T cells and NK cells than in the infected general *Conditions in which <100 patients were analysed. Data were obtained from population as well as remarkably lower serum levels of inflam- CDC COVID-19 Response Team [29]. matory cytokines than other COVID-19 patients [31]. Of note, 300 | L. D’Marco et al. As the main site of ACE2 expression is the brush border of context of systemic organ failure [39]. Among 701 patients with proximal tubular cells (https://www.proteinatlas.org/ COVID-19 admitted in a Wuhan hospital, at admission 44% had ENSG00000130234-ACE2/tissue/kidney; Figure 2B), it is likely proteinuria, 27% had haematuria and the prevalence of elevated that in the absence of viruria (and the few reports that serum creatinine, elevated urea and estimated glomerular fil- addressed this issue did not find it) or glomerular filtration of tration rate (eGFR) <60 mL/min/1.73 m2 was 14, 13 and 13%, re- the virus (unlikely given its 70–90 nm size), CD147 may repre- spectively. Additionally, 5% of patients developed AKI [39]. sent the key receptorfor kidney involvement of the virus. In cul- However, as discussed above, the study design could not distin- ture, SARS-CoV, the cause of SARS, leads to productive infection guish between pre-existent CKD and COVID-19-associated kid- in immortalized proximal tubular cells but not glomerular ney injury and there is evidence that CKD patients are at higher mesangial cell or podocytes [35]. Although the kidneys have risk of severe disease requiring hospitalization. higher ACE2 activity than the lungs, heart and pancreas [36], It is currently unclear to what extent the virus directly dam- heart and arterial smooth muscle cells also express ACE2 and ages renal cells or whether kidney injury is mainly secondary to may theoretically become infected. the cytokine storm syndrome [40]. Understanding the key Circulating and local renin–angiotensin–aldosterone system mechanisms of kidney injury in COVID-19 will have therapeutic (RAAS; including ACE2) are activated in kidney disease [37]. In implications. The cytokine storm has the potential to directly this regard, in different models of experimental diabetic ne- cause AKI, as supported by research in sepsis, endotoxemia, the phropathy, local kidney ACE2 is increased, reflecting largely tu- direct parenteral administration of inflammatory cytokines and bular cells that account for ~90% of kidney mass [38]. One may interventional studies [41]. It may be speculated that the inter- speculate that increased tubular cell ACE2 as a consequence of action of both processes may be most damaging: previously in- pre-existent pathological conditions may facilitate SARS-CoV-2 jured infected cells may be more sensitive to a deleterious infection of tubular cells. However, as data regarding the ACE2/ cytokine environment. Thus there is morphological and immu- SARS-CoV-2 interaction in kidney disease are scarce, it would nohistochemical evidence of SARS-CoV-2 infection of tubular be premature to speculate about intrarenal RAAS modulation of cells and podocytes. Potentially the contribution to kidney in- SARS-CoV-2 infection at this point. jury may differ at different stages of the natural history, with vi- AKI, proteinuria and haematuria have been reported in ral-induced tissue injury more prominent in early stages, when COVID-19-positive patients. AKI is usually observed in the lymphopaenia may contribute to viral expansion, and a more FIGURE 2: Kidney expression of cell receptors for SARS-CoV-2 according to the Protein Atlas. (A) CD147 immunostaining in normal human kidney (https://www.protei natlas.org/ENSG00000172270-BSG/tissue/kidney#img). (B) ACE2 immunostaining in normal human kidney (https://www.proteinatlas.org/ENSG00000130234-ACE2/tis sue/kidney). Note than CD147 is mainly expressed in the basolateral membrane of proximal and distal tubular cells while the main site of ACE2 expression is the brush border in the luminal side of proximal tubular cells. COVID-19 in chronic kidney disease | 301 prominent role of inflammation in more advanced stages. A hygienic measures as recommended by nephrological societies post-mortem report in COVID-19 patients who developed kid- for HD and transplanted patients [39, 54, 55]. ney failure suggests that coronaviruses directly infect kidney tu- There was some initial controversy regarding the need to bular cells, inducing acute tubular damage [35]. Moreover, there stop RAS blockade, which is widely prescribed to CKD patients. was CD68þ macrophage infiltration and complement C5b-9 de- ACE2 expression is increased in diabetes and treatment with position. Data are available for 26 autopsies of patients with ACE inhibitors and angiotensin II receptor blockers(ARBs) COVID-19 dying from respiratory failure associated with multi- increases ACE2 expression [56, 57]. It was thus hypothesized ple organ dysfunction syndrome, of whom 9 had developed in- that RAS blockade–induced ACE2 expression may facilitate creased serum creatinine and/or new-onset proteinuria. There COVID-19 infection [56]. Conversely, since ACE2 protects from was diffuse proximal tubule injury and red blood cell casts. experimental lung injury and recombinant ACE2 is undergoing Electron microscopy showed clusters of coronavirus particles in clinical trials for acute respiratory distress syndrome (28877748, the tubular epithelium and podocyte anti-SARS-CoV nucleopro- NCT00886353), it has been hypothesized that RAS blockade tein-stained tubules [42]. Of note, no viral load of SARS-CoV-2 in should be part of the therapeutic regimen for COVID-19 in order urine samples was found in the few studies that searched for it to increase ACE2 expression and its potential lung-protective in a small number of patients [43–45]. function [58]. There are no data regarding which of these medi- There is evidence for several potential mechanisms of kid- cations (ACE inhibitors or ARBs) are better in COVID-19 patients. ney injury, potentially depending on the severity of infection, In a multicentre retrospective evaluation of 511 patients with magnitude of the inflammatory response and even genetic COVID-19, in elderly (age >65 years) patients with hypertension, background. The most common mechanism based on both clin- the risk of severe disease was significantly lower in patients re- ical characteristics and histological studies is an acute tubular ceiving ARBs. However, in this older group of patients, only 10 necrosis form of AKI [42]. However, complement-mediated mi- were on ARBs [59]. In any case, there is an ongoing clinical trial crovascular injury, rhabdomyolysis-associated kidney injury of valsartan for prevention of acute respiratory distress syn- and collapsing glomerulopathy associated with apolipoprotein drome in hospitalized patients with COVID-19 (NCT04335786). L1 risk variants have been described, among others [19, 46]. In the absence of definitive evidence, some centres have opted for stopping RAS blockade in COVID-19 patients, while others follow clinical guidelines. In this regard, position statements from major societies have emphasized the lack of clinical evi- CKD, IMMUNE DYSFUNCTION AND COVID-19 dence that RAS blockade is deleterious for COVID-19 patients CKD causes marked alterations in the immune system, includ- and the overwhelming evidence that stopping RAS blockade ing persistent systemic inflammation and acquired immuno- may increase mortality acutely in cardiovascular disease suppression [47] (Figure 3). The most common alterations in the patients (https://www.eshonline.org/spotlights/esh-stabte immune system in CKD patients are characterized by B and T ment-on-covid-19, https://professional.heart.org/professional/ cell phagocytic dysfunction and increased concentrations of ScienceNews/UCM_505836_HFSAACCAHA-statement-addresses- pro-inflammatory cytokines and inflammatory monocytes [5, concerns-re-using-RAAS-antagonists-in-COVID-19.jsp). Recent 48]. These alterations progress as renal function declines. data support the safety of RAS blockade in COVID-19 [60, 61]. Regarding immune dysfunction in CKD, neutrophil function is When RAS blockade is prescribed for CKD from hypertension decreased in pre-dialysis and dialysis patients [49]. Likewise, B only and the patient is anxious because of social media reports, lymphocytes of advanced CKD patients have an increased rate RAS blockade may be more safely changed than in cardiovascu- of apoptosis that may contribute to B lymphopaenia [50]. T cells lar disease patients. from CKD patients have an aberrant state of early activation. Once CKD patients become infected, they should be quaran- Activated T cells may be driven to apoptosis, thereby contribut- tined and, if on HD, dialyzed by fully protected personnel and ing to T lymphopaenia, progressive immunodeficiency and the separated from non-COVID-19 patients, including transport to increased risk of infection observed in these patients [51]. the HD facility, while in the facitlity and back home. Criteria for Persistent inflammation, per se, is a risk factor for progression of hospital admission are very variable, depending on whether CKD and cardiovascular disease [52]. Multiple actors contribute hospitals are overloaded by COVID-19. In general, patients with to chronic inflammation in CKD, including patient-related fac- low oxygen saturation or bilateral pneumonia on chest X-ray tors, oxidative stress, infections and HD-related factors such as should be hospitalized. There is general agreement on support- biocompatibility and dialysate quality [53]. Thus there was a ive therapy. Thus adequate oxygenation, euvolemic state sur- correlation between the presence of microorganism DNA/RNA veillance, haemodynamic support and all those measures in the dialysate and oxidative stress and serum C-reactive pro- destined to prevent AKI or rapid progression of CKD should be tein and IL-6 [53]. considered in renal disease patients [39]. However, there is wide variability of therapeutic approaches for COVID-19-positive patients (Table 2). This is related to the lack of approved thera- pies. This variability includes decisions about treatment of indi- PREVENTION AND TREATMENT OF COVID-19 viduals that are not hospitalized. In this regard, in Spain, all IN CKD inpatients receive some therapy, but this is not always the case At present, there is no vaccine against COVID-19, although mul- for outpatients, even those with pneumonia. Potential compo- tiple human trials are ongoing (e.g. NCT04299724, NCT04276896, nents of the therapeutic cocktail in milder disease include anti- NCT04334980 and NCT04283461, among others). Moreover, viral drugs, non-antiviral drugs that may decrease viral there is no approved therapy for COVID-19 and all current ther- replication and low molecular weight heparin. Hospitalized apies should be considered experimental. Thus, although clini- patients usually have hyperinflammation and may receive dif- cal trials of chemoprophylaxis are also ongoing (e.g. ferent combinations of anti-inflammatory agents such as ste- NCT04328285, NCT04330495, NCT04304053, NCT04318015), pre- roids or anti-interleukin agents on top of the medication for vention relies mainly on social isolation and preventive milder cases. Thus Table 1 presents potential alternatives for 302 | L. D’Marco et al. A B C D FIGURE 3: Interaction between SARS-CoV-2 and CKD. (A) Infection by SARS-CoV-2 results in viral entry into cells and viral replication, causing tissue injury. Tissue in- jury is aggravated by a severe inflammatory response, eventually leading to death in some patients. (B) CKD is characterized by both evidence of immune deficiency, which may facilitate viral replication and expansion, and systemic inflammation, which may aggravate the hyperinflammation observed in more severe COVID-19 patients. (C) CKD is frequently associated with comorbidities that are dependent (e.g. anaemia, malnutrition and vitamin D deficiency) or associated (e.g. cardiovascu- lar disease and diabetes) with CKD. These comorbidities may also contribute to more severe disease, leading to death. Thus there is a biological plausibility supporting the empirical evidence of a higher mortality of COVID-19 in CKD patients. (D) Current therapy is aimed at decreasing viral replication and boosting antiviral defences, limiting hyperinflammation and supporting measures and thrombosis prevention. Currently these measures are similar for CKD and non-CKD patients. Research is needed for optimization and individualization of the therapeutic approach to the CKD state. therapy, but not all drugs are prescribed to the same individual. cyclosporine A include in vitro data showing inhibition of coro- Generally speaking, therapy for COVID-19-positive patients navirus replication, as this requires peptidyl-prolyl cis-trans with CKD is the same as in the general population. isomerase activity of cyclophilin [70, 71], as well as evidence of its efficacy in haemophagocytic lymphohistiocytosis, which may be a complication of COVID-19 [72]. However, it remains an Drugs targeting the virus immunosuppressive and nephrotoxic agent and protocols for Aerosolized IFN-a and lopinavir/ritonavir showed some benefit haemophagocytic lymphohistiocytosis suggest a delayed initia- in a Chinese trial (ChiCTR2000029308) but no benefit beyond the tion of cyclosporine A not compatible with the time course of standard care treatments in another report [65]. Similarly, the COVID-19. efficacy of chloroquine phosphate and remdesivir against COVID-19 has been tested in human cells and showed inhibi- tory properties for the virus [66]. Remdesivir was recently (1 Drugs targeting complications May 2020) authorized for emergency use in COVID-19 by the US Prophylactic low molecular weight heparin is the latest addition Food and Drug Administration based on preliminary clinical to the standard therapeutic package for COVID-19. Thus, be- trial results [67]. Moreover, hydroxychloroquine plus azithromy- yond venous thrombosis due to inactivity, large vessel arterial cin decreased SARS-CoV-2 viral load in COVID-19 patients [68]. thrombi and small vessel thrombi have been observed. However, this combination may increase the risk of long QT–as- Recently, anti-phospholipid antibodies were described [73]. sociated arrhythmia. Future therapeutic approaches Drugs targeting inflammation As discussed above, another interesting approach in COVID-19 Immunosuppressive treatment with short-term systemic corti- is to block the early stages of SARS-CoV-2 infection using hu- costeroids or monoclonal antibodies may decrease severe in- man recombinant soluble ACE2, and clinical trials are ongoing flammation [63]. Ongoing trials with convalescent plasma have [74, 75]. Very recently, investigators from Sweden, Canada, shown that early application in patients with COVID-19 could Spain and Austria described this new approach to the infection accelerate clinical recovery [69]. Arguments for the use of [76]. Infection of human blood vessels and kidney organoids by Table 2. General approach of some therapeutic approaches that have been used to treat COVID-19 Drug Mechanism of action Dose Administration CKD adjustment need Drugs targeting the virus IFN-a Stimulate innate antiviral 5 million U or equivalent dose, 2 Inhalation ESKD not recommended responses times/day Lopinavir/ritonavir Inhibit the 3-chymotrypsin-like 200 mg/50 mg capsule, 2 capsu- Oral Low renal clearance, no signifi- protease of SARS les each time, 2 times/day cant clearance in HD Remdesivir [62] Incorporates into nascent viral 200 mg once time, following by IV No data RNA chains and causes their 100 mg/day pre-mature termination Ribavirin Nucleoside analogues target the 500 mg, 2–3 times/day in combi- IV GFR 30–50 mL/min: 400 mg daily; RNA-dependent RNA polymer- nation with IFN-a or lopinavir/ GFR <30 mL/min: 200 mg ase and block viral RNA ritonavir daily. HD: 200 mg daily synthesis Darunavir/cobicistat Inhibitor of cytochrome P450 800/150 mg day Oral No data (CYP) 3A enzymes Chloroquine phosphate or Immune modulator with inhibi- 500 mg (300 mg for chloroquine), Oral Monitoring in GFR <15 mL/min: hydroxychloroquinea tory effects against COVID-19 2 times/day same doses but every 48 h 200 mg 2 times/day Not dialyzable Azithromycina Prevents viral production and vi- 500 mg/24 h or 500 mg/12 h Oral or IV No adjustment needed rus-mediated cell death Drugs targeting inflammation Tocilizumab Recombinant humanized mono- 8 mg/kg every 2–4 weeks; in IV No adjustment needed clonal IgG1 against human IL- COVID-19, frequently used as 6 receptor a single dose Sarilumab IL-6 receptor antagonist 200 or 400 mg day IV No data Anakinra Blocks activity of IL-1 a and b by 100–200 mg every 12–24 h IV Monitoring in GFR <15 mL/min: competitively inhibiting IL-1 every 48 h binding to the (IL-1RI) Cyclosporine A Inhibition of cytokines involved 2.5 mg/kg day divided into two Oral Monitoring serum levels in the regulation of T-cell doses (1.25 mg/kg per dose). activation Maximum dosage: 4 mg/kg day Drugs targeting complications Low molecular weight heparin Prevent large and small vessel Prophylactic dosing SC No adjustment needed thrombosis Different centres use different combinations of the drugs indicated above. Some are more widely used while others are only used at specific centres. There is currently no approved drug for COVID-19. Thus, informed consent should be obtained for the experimental use of these drugs. Adapted from Dong et al. [63] and Francisco Alm and Canga [64]. a Beware of increased risk of long QT–associated arrhythmia, especially if both are associated. In this regard, the dose of chloroquine should be adjusted if azithromycin is prescribed. COVID-19 in chronic kidney disease IV, intravenous; ESKD, end-stage kidney disease; IL-1RI, interleukin-1 type I receptor; SC, subcutaneous. | 303 304 | L. D’Marco et al. SARS-CoV-2 was significantly inhibited by recombinant soluble China: a retrospective cohort study. Lancet 2020; 395: ACE2 (rACE2) at the early stages of infection. Soluble rACE2 1054–1062 competes with cell membrane ACE2 for virus binding. Currently 7. Recalcati S. Cutaneous manifestations in COVID-19: a first a Phase 2 trial has started in 200 COVID-19 patients in Germany perspective. J Eur Acad Dermatol Venereol 2020; 34: e212–e213 and Austria (NCT04287686). Additionally, a Chinese trial is eval- 8. Tang N, Bai H, Chen X et al. Anticoagulant treatment is asso- uating NKG2D-ACE2 chimeric antigen receptor–NK cells ciated with decreased mortality in severe coronavirus dis- (NCT04324996). NKG2D is an activating receptor of NK cells, ease 2019 patients with coagulopathy. J Thromb Haemost which can recognize and thus clear virus-infected cells. 2020; 18: 1094–1099 Vitamin D has important functions beyond those of bone 9. Kurts C, Panzer U, Anders H-J et al. The immune system and and mineral homeostasis that include modulation of the innate kidney disease: basic concepts and clinical implications. Nat and adaptive immune responses. Vitamin D has pleiotropic Rev Immunol 2013; 13: 738–753 effects in the immune system and documented benefits in 10. Rubens J, Karakousis P, Sanjay J. Stability and viability of chronic inflammatory states such as those observed in CKD SARS-CoV-2. N Engl J Med 2020; 382: 1964 patients [77]. To date, the benefit of vitamin D supplementation 11. Lu R, Zhao X, Li J et al. Genomic characterisation and epide- in COVID-19 patients has not been demonstrated; nevertheless, miology of 2019 novel coronavirus: implications for virus ori- a clinical trial has been designed in Spain (NCT04334005). gins and receptor binding. Lancet 2020; 395: 565–574 It was recently postulated that extracorporeal membrane ox- 12. Wang K, Chen W, Zhou Y-S et al. SARS-CoV-2 invades host ygenation may help patients through non-specific removal of cells via a novel route: CD147-spike protein. bioRxiv 2020; circulating pro-inflammatory cytokines that cause the cytokine 10.1101/2020.03.14.988345 storm [78]. Therefore, continuous renal replacement therapies 13. Prompetchara E, Ketloy C, Palaga T. Immune responses in may play an important role in patients with COVID-19 and sep- COVID-19 and potential vaccines: lessons learned from sis syndrome. SARS and MERS epidemic. Asian Pac J Allergy Immunol 2020; 38: 1–9 14. Dounousi E, Papavasiliou E, Makedou A et al. Oxidative stress CONCLUSIONS is progressively enhanced with advancing stages of CKD. Am J Kidney Dis 2006; 48: 752–760 In conclusion, CKD patients are at an increased risk of develop- 15. Qin C, Zhou L, Hu Z et al. Dysregulation of immune response ing severe COVID-19. Moreover, the mortality rate appears to be in patients with coronavirus 2019 (COVID-19) in Wuhan, higher than in the general population and not always directly China. Clin Infect Dis 2020; https://academic.oup.com/cid/ad related to the severity of pulmonary compromise. This is not vance-article/doi/10.1093/cid/ciaa248/5803306 surprising, given that viral (e.g. influenza) or severe infection is 16. Giamarellos-Bourboulis EJ, Netea MG, Rovina N et al. associated with an increased risk of cardiovascular events both Complex immune dysregulation in COVID-19 patients with in the general population and in CKD patients [32, 33]. severe respiratory failure. Cell Host Microbe 2020; https://link Additionally, CKD patients frequently have cardiovascular and inghub.elsevier.com/retrieve/pii/S1931312820302365 diabetes comorbidities that may independently predispose to 17. Zhao J, Zhao J, Perlman S. Virus-specific regulatory T cells severe COVID-19. Given the absence of vaccine or approved ameliorate encephalitis by repressing effector T cell func- therapy, nephrologists should advise CKD patients to follow so- tions from priming to effector stages. PLoS Pathog 2014; 10: cial isolation recommendations directed at high-risk patients. e1004279 These should be extended to dialysis units, where a high index 18. Risitano AM, Mastellos DC, Huber-Lang M et al. Complement of suspicion and testing for COVID-19 should be implemented. as a target in COVID-19? Nat Rev Immunol 2020; http://www. Additionally, if healthcare systems are overwhelmed by the nature.com/articles/s41577-020-0320-7 pandemic, nephrologists should fight so that, despite the higher 19. Magro C, Mulvey JJ, Berlin D et al. Complement associated micro- risk, CKD is not considered a comorbidity that weighs down the vascular injury and thrombosis in the pathogenesis of severe patient’s chances to access ICU care or a respirator. COVID-19 infection: a report of five cases. Transl Res 2020; https:// linkinghub.elsevier.com/retrieve/pii/S1931524420300700 20. Diurno F, Numis FG, Porta G et al. Eculizumab treatment in CONFLICT OF INTEREST STATEMENT patients with COVID-19: preliminary results from real life None declared. ASL Napoli 2 Nord experience. Eur Rev Med Pharmacol Sci 2020; 24: 4040–4047 21. Mastaglio S, Ruggeri A, Risitano AM et al. 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