Clinical Kidney Journal, 2021, vol. 14, Suppl 1, i21–i29 doi: 10.1093/ckj/sfab030 CKJ Review Clinical Kidney Journal CKJ REVIEW Kidney transplantation and COVID-19 renal and patient prognosis Néstor Toapanta1,2, Irina B. Torres1,2, Joana Sellarés1,2, Betty Chamoun1,2, Daniel Serón1,2 and Francesc Moreso1,2 1 Department of Nephrology, Hospital Universitari Vall d’Hebron, Barcelona, Spain and 2Department of Medicine, Autonomous University of Barcelona, Barcelona, Spain Correspondence to: Francesc Moreso; E-mail: fjmoreso@vhebron.net ABSTRACT Coronavirus disease 2019 (COVD-19) emerged as a pandemic in December 2019. Infection has spread quickly and renal transplant recipients receiving chronic immunosuppression have been considered a population at high risk of infection, complications and infection-related death. During this year a large amount of information from nationwide registries, multicentre and single-centre studies have been reported. The number of renal transplant patients diagnosed with COVID- 19 was higher than in the general population, but the lower threshold for testing may have contributed to its better identification. Major complications such as acute kidney injury and acute respiratory distress syndrome were very frequent in renal transplant patients, with a high comorbidity burden, but further studies are needed to support that organ transplant recipients receiving chronic immunosuppression are more prone to develop these complications than the general population. Kidney transplant recipients experience a high mortality rate compared with the general population, especially during the very early post-transplant period. Despite the fact that some studies report more favourable outcomes in patients with a kidney transplant than in patients on the kidney waiting list, the higher mortality described in the very early post-transplant period would advise against performing a kidney transplant in areas where the spread of infection is high, especially in recipients >60 years of age. Management of transplant recipients has been challenging for clinicians and strategies such as less use of lymphocyte-depleting agents for new transplants or anti-metabolite withdrawal and calcineurin inhibitor reduction for transplant patients with COVID-19 are not based on high-quality evidence. Keywords: acute kidney injury, acute respiratory distress syndrome, COVID-19, mortality, renal transplantation, SARS-CoV-2 INTRODUCTION (https://coronavirus.jhu.edu/map.html; accessed 28 November Coronavirus disease 2019 (COVID-19) is caused by the single- 2020). There was an initial wave during March and April 2020 strand RNA virus called severe acute respiratory syndrome co- until a lockdown was ordered by many national governments. ronavirus 2 (SARS-CoV-2) and has become a worldwide threat. After progressive lifting of the lockdowns, a second wave is The first human case of COVID-19 was reported in Wuhan, evolving, with the USA, India, Brazil, Russia, France and Spain China, in December 2019, and within a few weeks the infection having the highest rates of infection. Fever, fatigue and dry spread around the world, becoming a pandemic [1]. A total of cough are the most common symptoms and patients may also >62 million people have been diagnosed and 1.45 million died experience shortness of breath, myalgia, sore throat and Received: 1.12.2020; Editorial decision: 27.01.2021 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 i21 i22 | N. Toapanta et al. gastrointestinal (GI) symptoms [2]. Reverse transcription poly- Tests to detect antibodies against SARS-CoV-2 were incorpo- merase chain reaction (RT-PCR) is the gold standard for rated into clinical practice later and they allow characterizing diagnosis. Treatment is based on oxygen supply and a the proportion of asymptomatic or pauci-symptomatic patients combination of drugs that have evolved during the pandemic. not screened by RT-PCR. In a large study conducted in the Bronx Initially drugs with potential antiviral activity (e.g. lopinavir/ri- borough of New York City, the combination of RT-PCR and anti- tonavir, hydroxychloroquine) were widely used, but later, ran- bodies characterized an incidence as high as 234/1000 trans- domized prospective trials demonstrated their lack of efficacy plant patients, with 41% diagnosed only by the presence of [3] and only remdesivir has been approved by regulatory agen- antibodies against SARS-CoV-2 [19]. For symptomatic patients cies to treat COVID-19 [4]. Now the agents being studied to miti- (PCR positive), the hospitalization rate was high (84.1%), while gate the clinical impact of this infection and decrease its for the overall cohort it was lower (48.5%). severity are focused on immune mediators, stem cells and Thus, although the number of renal transplant patients di- agents intended specifically to improve or support lung function agnosed with COVID-19 was higher than in the general popula- (https://www.wcgclinical.com/covid-19/covid-19-trial-insights). tion, the lower threshold for testing may have contributed to its Renal transplant patients have been one of the populations better identification while many oligosymptomatic individuals most vulnerable to COVID-19 and many reports have been pub- in the general population were not tested and do not appear in lished. In this setting, immunomodulation has emerged as a the official statistics [10]. promising option for patients with COVID-19-related cytokine The mean age of renal transplant patients with COVID-19 storm, but the supporting evidence is scarce and of low quality was 60 years and the proportion of males (two-thirds) and [5]. Moreover, COVID-19 has had a big impact on wait-listed comorbidities (arterial hypertension >80%, diabetes >25%) cor- patients, highlighting the need to properly balance the risks and relates with the characteristics of transplanted patients. Clinical presentation is characterized by fever, cough and short- benefits of transplantation in the setting of an ongoing ness of breath in >60% of patients, while GI symptoms were de- pandemic [6]. scribed in about one-third of patients [20]. The aim of this article is to review the available literature published until now regarding renal and patient prognosis in renal transplant patients with COVID-19. AKI IN RENAL TRANSPLANT PATIENTS WITH COVID-19 EPIDEMIOLOGY OF COVID-19 IN RENAL Acute kidney injury (AKI) is a common complication in patients TRANSPLANT PATIENTS ACROSS THE WORLD with COVID-19 and is associated with increased intensive care unit (ICU) admission and mortality [21, 22]. AKI incidence is Since the outbreak, a lot of information has been available from higher in patients admitted to the ICU due to COVID-19 than in nationwide registries and multicentre and local studies. A patients admitted for other reasons [23]. In a large retrospective European study conducted by the ERA-EDTA from the French study (9657 patients), 39.9% developed AKI, of which 6.6% re- and Spanish registry yielded an average infection rate of 14/ quired renal replacement therapy (RRT) [24]. Approximately 1000 transplants at risk [7]. The Spanish registry [8], with a lon- one-third of patients with AKI do not fully recover renal func- ger period of observation, showed an incidence of 17.7/1000 tion [25]. The main risk factors associated with AKI are ad- transplants, while the French registry [9], with a shorter obser- vanced age, male gender, severity of respiratory impairment, vation period, showed an incidence of 9.5/1000 transplants. The mechanical ventilation, pre-existing chronic renal failure, co- kidney registry of the Dutch-speaking Belgian Society of infection with other organisms and systemic inflammatory re- Nephrology reports a similar incidence of 14.0/1000 transplants sponse [22–24]. Noticeably, AKI was increased in the subgroups [10]. Similar incidences were reported from multicentre studies with diabetes compared with subgroups without this condition including patients from the USA, Italy and Spain [11, 12]. [26]. A group to highlight is patients of African descent, in Importantly, the incidence during the observation periods was whom a greater risk of COVID-19 infection has been described 2–5 times higher in renal transplants than in the general popu- [22, 27, 28]. In this population, the APOL1 genotype is closely re- lation. Even in small countries like Scotland with a lower lated to the development of nephropathy and evidence suggests COVID-19 incidence, with only 24 transplant patients diagnosed that the SARS-CoV-2 infection could act as a ‘second blow’ that with COVID-19, the incidence was 3 times that of the general leads to podocyte dysregulation [29]. population [13]. However, single-centre analysis conducted in Considering that kidney transplant patients have a single areas with a high rate of infection revealed higher incidences functional kidney, receive a tacrolimus-based regimen that has [14–16]. A summary of the larger studies conducted is shown in nephrotoxic effects [30], have a high prevalence of hypertension Table 1. During the initial wave there were no studies providing and diabetes [31] and that Black race increases the risk of AKI in information about asymptomatic patients since they were not kidney recipients [32, 33], a higher incidence and severity of AKI generally screened. During the first wave, the hospitalization in these settings would be expected. However, few studies have rate of symptomatic patients with COVID-19 was >80% in the attempted to compare AKI in kidney transplant patients with nationwide registries and multicentre studies (Table 1). the general population. Aziz et al. [34] reviewed 19 articles Likewise, in a cohort of 44 patients with mild symptoms, 34 reporting AKI incidence in kidney transplant and non- needed to be referred to the emergency department and man- transplanted patients. Despite the fact that AKI incidence was aged as inpatients while only 9 patients with suspected COVID- higher in kidney transplant patients (27.5% versus 13.3%), as 19 (never tested due to limitations) were managed as outpa- well as RRT (15.4% versus 3.3%), the mortality rate was similar tients, and the only patient with confirmed COVID-19 was never between groups. In a systemic review conducted by Marinaki et hospitalized [17]. Finally, in a cohort of 41 patients, the hospital- al. [35] including 420 patients, 44% of hospitalized kidney trans- ization rate was 55% for those patients with confirmed COVID- plant patients developed AKI and 23% required RRT. In a multi- 19 while it was 5% for suspected but never tested patients [18]. centre study including 104 hospitalized kidney transplant Kidney transplantation and COVID-19 | i23 Table 1. Incidence of COVID-19 in nationwide registries and multicentre or single-centre studies Incidence of Time frame RT with RT/1.000 Incidence of Relative Hospital Reference Registry (2020) COVID-19 (95% CI) GP/1.000 risk (95% CI) admission (%) Jager et al. [7] ERA-EDTAa 1 February–30 April 1013 14 (13–16) 2.7 5.23 – (4.92–5.56) Coll et al. [8] Spain 20 February–13 July 621 17.7 5.5 3.22 90.1 (16.4–19.2) (2.98–3.45) Caillard et al. [9] France 1 March–21 April 426 9.5 1.7 5.67 87.1 (8.6–10.4) (5.16–6.23) De Meester Belgium 2 March–25 May 46 14.0 6.4 2.20 82.6 et al. [10] (Flandes) (10.5–18.6) (1.65–2.93) Bell et al. [13] Scotland 1 March–31 May 24 8.3 2.8 2.98 – (5.9–11.8) (2.11–4.21) Cravedi et al. [11] TANGO 2 March–15 May 144 14.7 – 100 Consortiumb (12.2–17.2) Fava et al. [12] Catalonia 4 March–17 April 112 15.8 – – 97.3 Albacetec (13.1–19.0) Bossini et al. [15] Brescia (Italy) 1 March–16 April 53 44.2 – – 84.9 (33.9–57.3) Elias et al. [14] Parisd 1 March–30 April 66 54.3 – – 90.9 (42.9–68.5) Crespo et al. [16] Barcelonee 12 March–4 April 16 49.4 – – 100 (30.6–78.7) Mehta et al. [17] New York- 16 March–2 June 228 234 – – 84.1 Bronxf (209–262) RT with COVID-19: number of renal transplant patients diagnosed with COVID-19; Incidence RT: incidence of COVID-19 in renal transplant patients per 1000 patients at risk provided by national registries; Incidence in GP: incidence of COVID-19 in the general population provided by the national registries. The relative risk of renal transplants versus general population was calculated by standard formulas. a The ERA-EDTA registry only includes renal transplants from Spain and France in this report. b TANGO consortium: 12 centres from the USA (n ¼ 6), Italy (n ¼ 4) and Spain (n ¼ 2). c Renal transplants managed in four hospitals from Catalonia and Albacete (Spain). d Prospective study in renal transplant patients managed at Hospital Saint Louis and Hospital Bichat from Paris (France). e Renal transplant patients >65 years of age managed by Hospital del Mar from Barcelona (Spain). f Symptomatic patients diagnosed by RT-PCR (n ¼ 132) and by serology (n ¼ 96). Hospitalization rate for the overall cohort was 48.5% (111 of 228 patients). Table 2. Incidence of AKI and need for RRT in hospitalized kidney transplant and non-transplanted patients hospitalized due to transplant patients and in the general population with COVID-19 COVID-19 infection. infection If we consider the incidence of AKI in the general population and in kidney transplant patients, available data do not clearly No. of patients % AKI % RRT support a higher incidence of AKI in transplanted patients. Kidney transplantation However, this statement should be taken with caution since Marinaki et al. [33] 345 44.0 9.9 more information is needed, especially, in kidney transplant Favá et al. [12] 104 45.0 Not reported patients. Cravedi et al. [11] 144 52.0 Not reported Elias et al. [14] 66 42.0 11.0 Weighted average 659 45.7 10.1 AKI AND HISTOLOGY General population Acute tubular necrosis is the main finding in patients with AKI Chan et al. [25] 3993 46.0 8.7 [36, 37]. However, a high proportion of patients display protein- Fisher et al. [23] 3345 56.9 4.9 uria (44–66%) and microhaematuria (27–42%), suggesting that, in Richardson et al. [26] 2351 22.2 3.2 addition to classical factors leading to AKI, a direct cytopathic Ng et al. [24] 9657 39.9 6.6 Weighted average 19 346 41.9 6.3 effect of the virus may contribute to renal damage [21, 38]. Angiotensin-converting enzyme 2 receptor is highly expressed Incidence of AKI in studies including >1000 patients from the general popula- in kidney podocytes and tubular cells, and viral particles have tion and studies including >50 kidney transplant patients. The incidence of AKI been observed in electron microscopy studies [36, 38, 39]. In the and the need for RRT was summarized as the weighted average. vast majority of patients, haematuria and proteinuria rapidly disappeared; however, in patients with severe proteinuria, collapsing glomerulopathy [40–45], minimal change disease, patients, AKI was observed in 47% of patients and, interestingly, thrombotic microangiopathy [46, 47] and pauci-immune cres- it was observed that tacrolimus trough levels were higher in centic glomerulonephritis [48] have been described. patients with Stage 3 AKI. However, AKI or Stage 3 AKI were not In kidney transplant patients there is scarce information on associated with mortality [12]. Table 2 describes the incidence histological findings. In patients with AKI, apart from acute tubu- of AKI and the proportion of patients requiring RRT in kidney lar injury, minimal change disease [49], cortical necrosis [50] and i24 | N. Toapanta et al. collapsing glomerulopathy [51–53] have also been described. In ad- Table 3. Incidence of ARDS in hospitalized kidney transplant recipi- dition, very few cases of T cell– or antibody-mediated rejection ents and the general population with COVID-19 infection have been described, raising the question of whether COVID-19 in- No. of fection may enhance the alloimmune response [46, 50]. References patients % ARDS % Severe Kidney transplantation ACUTE RESPIRATORY DISTRESS SYNDROME Coll et al. [8] 375 35.7 Not reported (ARDS) IN RENAL TRANSPLANT PATIENTS Cravedi et al. [11] 144 29.0 Not reported WITH COVID-19 Favà et al. [12] 104 54.8 16.3 Bossini et al. [15] 45 60.0 Not reported In the general population, the spectrum of COVID-19 varies Elias et al. [14] 66 68.0 Not reported widely, from asymptomatic to pneumonia and life-threatening Cavalcanti et al. [66] 36 39.0 Not reported complications, including ARDS, multisystem organ failure and Weighted average 770 41.4 16.3 ultimately death. ARDS occurs because of an acute systemic in- General population flammatory response that can be caused by insults to the lung, Petrilli et al. [58] 1099 16.7 72.9 either direct or indirect. The reported incidence of ARDS in the Richardson et al. [26] 2634 12.2 Not reported general population is 12–31%, being severe in 56–79% of cases Berengue et al. [59] 2741 23.6 60.4 [26, 54–60]. Age and the presence of comorbidities are the main Cummings et al. [60] 3979 31.5 67.4 risk factors for developing ARDS [61]. Wu et al. [61] 1150 22.0 79.0 Kidney transplant recipients may be at high risk of develop- Weighted average 11 603 21.2 55.6 ing severe COVID-19 disease due to chronic immunosuppres- Incidence of ARDS in studies including >1000 patients from the general popula- sion, comorbidities and frequent contact with the healthcare tion and studies including >30 kidney transplant patients. The incidence of system. Indeed, they may be more likely to be diagnosed when ARDS and its severity was summarized as the weighted average. they have symptoms due to closer follow-up at the transplant centre [8, 62–64]. However, there are few studies comparing Despite the high incidence of ARDS in the transplanted ARDS in kidney transplant patients and the general population. population and its deleterious consequences, more detailed In a study conducted at our centre [63], 46 solid organ transplant studies are neeeded to support that organ transplant recipients (SOT) recipients (30 renal transplants) admitted due to COVID- receiving chronic immunosuppression are more prone to de- 19 were matched by age, sex and age-adjusted Charlson comor- velop ARDS than the general population. bidity index to 166 controls. As expected, hypertension and During the first wave of the pandemic, the most widely used chronic kidney disease were more frequent in transplant recipi- agents with presumed antiviral activity were hydroxychloroquine, ents. A total of 27 (58.7%) transplant recipients and 71 (42.8%) antibiotics (azithromycin) and protease inhibitors, showing no controls suffered progressive respiratory failure. In a similar benefit for prevention or treatment in both the general [54, 66–68] study conducted in Michigan, 41 SOT recipients (67% were and SOT populations [8, 9, 11, 12, 14, 15], and increasing the risk Black; 16 single and 5 combined kidney transplants) were of interactions with other drugs [63, 69]. In the general population, matched by age, race and admission status to 121 controls [32]. remdesivir has been shown to decrease the in-hospital stay, but Severe disease-adjusted risk of death was similar in both with no effect on the mortality rate. Importantly, its use is con- groups and the severity of COVID-19 and number of intubations traindicated in patients with an estimated glomerular filtra- were also similar, but the incidence of AKI requiring RRT was tion rate (eGFR) <30 mL/min/1.73 m2 and there are no studies higher in transplant patients (29.3% versus 5.8%). on the use of remdesivir in the transplanted population [70]. Data from multicentre studies yielded similar results; It has been shown that besides viral evasion to immune re- Cravedi et al. [11] identified 144 hospitalized adult kidney trans- sponse, cytokine storm plays an important role in COVID-19 dis- plant recipients and 29% required orotracheal intubation. A ease progression. Thus efforts have been made to mitigate the Spanish multicentre kidney transplant study with 104 hospital- immune response with immunomodulators and large reviews ized patients reported that 54.8% developed ARDS and that exist on the potential role, efficacy and safety of these agents in it was associated with obesity [odds ratio (OR) 2.63; P ¼ 0.04] [12]. the management of severe COVID-19 [71, 72]. Non-randomized No significant age difference was found between patients who studies have shown that treatment with tocilizumab in criti- developed or did not develop ARDS; however, the elderly may cally ill patients may offer some benefit in both the general [73] have a higher risk of death. Bossini et al. [15] found that in 45 and kidney transplant population [74]. However, prospective patients admitted to the hospital due to severe symptoms, 60% randomized studies in hospitalized patients with COVID-19 developed ARDS. A trend for an increased risk of ARDS was pneumonia showed that although tocilizumab may reduce the recorded in patients on tacrolimus fOR 2.77 [95% confidence in- likelihood of progression to mechanical ventilation, it did not terval (CI) 0.91–8.9]g, whereas a protective trend towards the improve survival [75, 76]. Importantly, the large RECOVERY trial risk of ARDS was a transplant vintage >10 years [OR 0.37 [95% CI showed that dexamethasone decreases 28-day mortality among 0.12–1.1]) and the presence of GI symptoms at disease onset [OR those who were receiving either invasive mechanical ventila- 0.21 (95% CI 0.04–1.1)]. Similarly, Akalin et al. [65] reported an ini- tion or oxygen alone, but not among those receiving no respira- tial series of 36 patients with COVID-19; 28 were admitted to the tory support [77]. Thus research efforts should focus not only on hospital and 27 (96%) had radiographic findings that were con- the most relevant immunomodulatory strategies, but also the sistent with viral pneumonia. Eleven of 27 (39%) required me- optimal timing of such immunomodulatory interventions to chanical ventilation and 7 of them (64%) died. Table 3 describes maximize the therapeutic effect [71]. the incidence of ARDS and its severity in kidney transplant In kidney transplantation, the most widely used interven- patients and in the general population hospitalized for COVID- tions were the modification of immunosuppression, reducing or 19 infection. suspending the antimetabolite or inhibitors of the mammalian Kidney transplantation and COVID-19 | i25 target of rapamycin, while the calcineurin inhibitor was as C-reactive protein, interleukin-6 (IL-6), D-dimer or serum lac- suspended in patients at risk for interaction with protease tate dehydrogenase [8, 12, 74, 82]. Interestingly, in a Turkish co- inhibitors [8, 11, 12, 66, 78]. Recently, the in vitro efficacy of cy- hort of 40 renal recipients, the use of previous antirejection closporine A and FK506 to inhibit the replication of SARS-CoV-1 treatment was an independent predictor for mortality and the and other human coronaviruses has been reported [79]; use of cyclosporine as a maintenance immunosuppressant was however, there is no clinical evidence for a protective effect to associated with better survival [85]. Likewise, in a study that in- reduce the likelihood of severe COVID-19 or to treat the cytokine cluded 29 renal transplant patients, patients on cyclosporine- storm. Also, there is no evidence on what the management of based immunosuppression experienced less mortality com- immunosuppression should be. An approach like that of other pared with immunosuppression minimization [86]. serious viral infections (mycophenolate withdrawal and calci- The Spanish registry included 423 kidney transplants with a neurin inhibitor reduction) seems a safe option since this mortality rate of 28% [8]. Interestingly, the mortality rate de- change in immunosuppression has been associated with very clined to 15.8% after adjusting for age and gender, implying that low incidences of acute rejection. baseline characteristics rather than the immunosuppressive state or the transplant itself has a remarkable effect on survival. Overall, the risk of death increased with age (>60 years) and PATIENT MORTALITY AND RISK FACTORS FOR mortality was higher among recipients who developed ARDS DEATH IN RECIPIENTS WITH COVID-19 and in those with nosocomial COVID-19. No differences were A British population-based study showed that SOT patients had found regarding baseline immunosuppression between survi- one of the highest in-hospital risks of death (HR 4.23) due to vors and non-survivors, but in patients with ARDS in whom the COVID-19 [80]. In a large multicentre US study (423 SOT patients, antimetabolite agent was discontinued, the mortality was lower including 318 kidney or kidney–pancreas recipients), the overall [8]. A French registry–based study that included 279 renal trans- mortality rate by Day 28 was 20.5% among the hospitalized plant patients reported a mortality rate of 22.8% and indepen- patients and 18.5% among the overall cohort [62]. Risk factors dent risk factors for mortality included age >60 years, for mortality included age >65 years, chronic heart failure, cardiovascular disease and dyspnoea [9]. chronic lung disease and obesity. Also, the presence of pneumo- In the TANGO multicentre study (144 hospitalized kidney nia and lymphopaenia at diagnosis were independently associ- transplants), the mortality rate was 32% and older age, lower ated with mortality. Of interest, none of the multiple surrogates lymphocyte counts, higher lactate dehydrogenase, procalcito- for immunosuppression that were explored showed any associ- nin and IL-6 levels and lower eGFR were associated with mortal- ation with mortality. ity [11]. Moreover, the presence of dyspnoea at onset (61% Focusing on renal transplants, a recent systematic review versus 83%) was associated with mortality while the presence of based on 20 studies from different countries revealed a patient diarrhoea was more frequent in survivors (45% versus 24%). mortality higher than in general population, ranging between Other factors such as the type of transplantation (living versus 18% and 43% [81]. Risk factors associated with mortality deceased donor), time post-transplantation (<1 versus >1 year), (Table 4) included older age [13, 15, 74, 82–84], plasma viral load comorbidities or type of immunosuppression were not associ- [82] and the presence of higher inflammatory biomarkers such ated with mortality. None of the treatment strategies with Table 4. Risk factors independently associated with mortality in renal transplant recipients with SARS-CoV-2 infection Variable References Reference group Relative risk 95% CI Age Craig-Shapiro et al. [6] >60 years 4.0 1.4–11.2 Coll et al. [8] >60 years 3.7 2.5–5.5 Caillard et al. [9] >60 years 3.8 1.6–9.3 Cravedi et al. [11] >60 years 2.6 1.3–5.8 Benotmane et al. [82] >60 years 4.3 1.9–10.2 Favà et al. [12] Per year 1.10 1.05–1.16 Ravanan et al. [83] Per year 1.07 1.04–1.09 Gender Craig-Shapiro et al. [6] Male 5.7 1.5–21.7 Immunosuppression Williamson et al. [80] Rejection treatment 9.7 1.2–77.7 Cyclosporine 0.08 0.02–0.32 Nosocomial COVID-19 Coll et al. [8] Yes 3.0 1.9–4.9 Dyspnoea at onset Cravedi et al. [11] Yes 3.1 1.3–1.7 Fava et al. [12] 4.2 1.6–11.2 Caillard et al. [9] 2.3 1.2–4.5 Diarrhoea at onset Cravedi et al. [11] Yes 0.4 0.2–0.9 Acute respiratory Coll et al. [8] Yes 28.9 17.6–47.4 distress syndrome Fava et al. [12] Yes 2.1 1.03–8.23 Lactate dehydrogenase Cravedi et al. [11] >325 U/L 3.5 1.6–7.8 Fava et al. [12] UI/L 1.003 1–1.005 C-reactive protein Fava et al. [12] mg/L 1.003 1.002–1.005 Pro-calcitonin Cravedi et al. [11] >0.5 ng/mL 3.0 1.4–6.9 eGFR Cravedi et al. [11] mL/min 0.97 1.07–3.9 Cardiovascular disease Caillard et al. [9] Yes 2.04 1.07 3.9 Diabetes Craig-Shapiro et al. [6] Yes 2.97 1.03–8.57 i26 | N. Toapanta et al. antivirals used to treat COVID-19 had any impact on survival. the early outbreak period, general recommendations from the Again, patients with nosocomial SARS-CoV-2 infection had the different societies in areas in which the virus was widespread highest mortality rate (77.8%) [11]. implied avoiding living-donor transplantation and reserving In a multicentre study from Spain that included 104 kidney deceased-donor transplantation for life-threatening conditions recipients, the mortality rate was 28% and older age, higher se- or for hypersensitized patients with a suitable donor [96–98]. In rum lactate dehydrogenase and having ARDS at admission were this pandemic scenario, there are several studies that aimed to independently associated with a higher risk of death [12]. address whether it would be safer to undergo a renal transplan- A Belgium registry–based study that included 46 kidney tation or remain on the waiting list. In a single-centre study in transplant recipients with COVID-19 showed a mortality similar which the outcomes of 56 patients included on the waiting list to that reported in the general population (14% versus 15.3%), were compared with the outcomes of 80 kidney transplant but much lower than in patients on dialysis (14% versus 29%) recipients, wait-listed patients with COVID-19 were not only [10]. more likely to require more hospitalization (82% versus 65%), In another study that involved several European countries but also had an increased risk of death (25% versus 16%), with (ERACODA), 305 renal transplant patients were included, with a comparable baseline demographics and comorbidities between 28-day mortality rate of 21.3% as compared with 25% in patients groups [6]. In this cohort, risk factors independently associated on dialysis, and older age was the predominant risk factor for with mortality were wait list status, male sex, age and diabetes. mortality in renal recipients [87]. On the same note, in a registry-based study from France in Most of the available data on survival involves long-term which renal transplant recipients and patients included on the stable recipients, and there is scarce information regarding waiting list were compared in different time periods, an in- early transplant recipients. In studies in which the subgroup of crease in deaths was detected in both populations between early transplant recipients was analysed for <6 months [12] or March and June 2020 as compared with the same period in the <1 year [12, 88], mortality was not different between groups, al- two previous years [99]. This was explained by COVID-19, which though in some of them there was a trend towards a higher caused the deaths of 44% of recipients and 42% of wait-listed mortality for the early group [12]. A recent report that included patients. Interestingly, the increase in risk of death in both pop- 24 recipients with COVID-19 diagnosed within 60 days after ulations was similar in high-risk geographic areas, but in low- transplantation revealed a significant impact on patient sur- risk areas the risk of death in wait-listed patients 4-fold higher, vival with a mortality rate of 46% [89]. Recipients who died were but there was no additional risk for renal transplant recipients, suggesting that transplant programmes should not be sus- older (61 versus 70 years), received high-dose steroids less fre- pended in geographic areas with a low spread of infection. In a quently (25% versus 82%) and usually needed ventilation sup- multicentre study in London, an area with a high prevalence of port (15% versus 78%). In another study that included 237 COVID-19 [100], outcomes after SARS-CoV-2 infection in kidney patients in the first-year post-transplant, of whom 16 had a transplant recipients (n ¼ 121) were compared with patients on COVID-19 diagnosis, the mortality rate was 37% [90]. the waiting list (n ¼ 51). Although no differences in mortality In this pandemic era, management of induction and mainte- were found (30% versus 27%), the only risk factor independently nance immunosuppression has been challenging to clinicians associated with mortality was being >60 years of age in the kid- treating kidney transplant patients. Regarding the use of induc- ney transplant group [OR 4.3 (95% CI 1.8–10.2)] [88]. Finally, in tion therapy with lymphocyte-depleting agents (anti-thymocyte contrast with the previous data, there is a single-centre study globulins, alemtuzumab and rituximab), a large study con- performed in London in which the overall survival on a popula- ducted in the USA showed that their use decreased during the tion level between wait-listed and kidney transplant patients first several weeks of the pandemic compared with the three was not different, but the mortality rate following SARS-CoV-2 previous years, while the use of basiliximab or no induction in- infection was higher in the renal transplant group (37% versus creased. Importantly, during the pandemic, lymphocyte- 11%) [90]. Few studies exist in the paediatric population, but the depleting agents were associated with a lower risk of acute re- available data support that since chronic immunosuppression jection, but without significant differences in mortality. These is not associated with an increased risk of COVID-19 in young results question whether this shift in induction immunosup- kidney transplant patients, transplant activity should be main- pression was a safe and effective approach to address the novel tained even in areas with a high incidence of SARS-CoV-2 infec- infectious risk [91]. Additionally, small studies conducted in tion [101]. single centres show that renal transplant patients treated with thymoglobulin who acquired the COVID-19 infection early after transplantation had a modest risk for severe disease [92], espe- CONCLUSIONS cially using low doses [93]. However, it seems prudent to moni- The COVID-19 pandemic has been challenging for kidney trans- tor absolute lymphocyte count following lymphocyte-depleting plantation programmes around the world, with a big impact on induction and consider temporary an antimetabolite dose re- transplant policies and in the management of infected and duction in patients with severe lymphopaenia [92]. Conversely, uninfected patients. The rate of infected transplants was high management of steroids was not modified in the USA during in geographic areas with widespread infection and patient out- the pandemic and the practice of steroid avoidance/withdrawal comes were compromised due to high rates of complications has not been modified and its use did not modify the graft fail- and COVID-19-related deaths. In managing infected patients ure or mortality rates [91]. during the pandemic, only the use of steroids and remdesivir has been demonstrated to be useful after performing random- OUTCOMES IN KIDNEY RECIPIENTS VERSUS ized controlled clinical trials. Since chronic immunosuppression may influence a patient’s outcome, different changes based on PATIENTS ON THE WAITING LIST art and theory were applied. Thus, in the absence of trial-based Since the beginning of the pandemic, all transplant pro- evidence, we should include transplant patients in prospective grammes have dramatically reduced their activity [94, 95]. In studies and registries to help guide optimal care [102]. Kidney transplantation and COVID-19 | i27 FUNDING experience from the Scottish renal registry. BMC Nephrol 2020; 21: 419 The authors received grants from Red de Investigación 14. Elias M, Pievani D, Randoux C et al. COVID-19 infection in Renal (REDinREN RD16/0009/0030) and Fondo de kidney transplant recipients: disease incidence and clinical Investigación Sanitaria del Instituto de Salud Carlos III (PI outcomes. J Am Soc Nephrol 2020; 31: 2413–2423 18/01704, PI 18/01382). B.C. is supported by a Vall d’Hebron 15. Bossini N, Alberici F, Delbarba E et al. Kidney transplant Institute of Research grant. This article is part of a supple- patients with SARS-CoV-2 infection: the Brescia Renal ment supported by Fresenius Medical Care without any COVID task force experience. Am J Transplant 2020; 20: influence on its content. 3019–3029 16. Crespo M, Pérez-Sáez MJ, Redondo-Pachón D et al. COVID- 19 in elderly kidney transplant recipients. Am J Transplant CONFLICT OF INTEREST STATEMENT 2020; 20: 2883–2889 The authors declare no conflicts interest. 17. Mehta SA, Leonard J, Labella P et al. 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