16006143, 2020, 11, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ajt.

16141 by Spanish Cochrane National Provision (Ministerio de Sanidad), Wiley Online Library on [19/10/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
| |
Received: 28 April 2020    Revised: 26 May 2020    Accepted: 8 June 2020

DOI: 10.1111/ajt.16141

B R I E F C O M M U N I C AT I O N

Should cyclosporine be useful in renal transplant recipients

affected by SARS-CoV-2?

Beatriz Rodriguez-Cubillo1  | Maria Angeles Moreno de la Higuera1 | Rafael Lucena1 |

Elena V. Franci1 | Maria Hurtado1 | Natividad C. Romero1  | Antolina R. Moreno1 |
Daniela Valencia1 | Mercedes Velo1 | Iñigo S. Fornie2 | Ana I. Sanchez-Fructuoso3

1
Nephrology Department, Hospital Clinico
San Carlos, Madrid, Spain Minimization of immunosuppression and administration of antiretrovirals have
2
Internal Medicine Department, Hospital been recommended for kidney transplant recipients (KTRs) with coronavirus dis-
Clinico San Carlos, Madrid, Spain
ease 2019 (COVID-19). However, outcomes remain poor. Given the likely benefit of
3
Nephrology Department, Hospital
Clinico San Carlos, University of Medicine
cyclosporine because of its antiviral and immunomodulatory effect, we have been
Complutense de Madrid, Madrid, Spain using it as a strategy in KTRs diagnosed with severe acute respiratory syndrome

Correspondence
coronavirus 2 (SARS-CoV-2). We studied 29 kidney transplant recipients (KTRs) who
Beatriz Rodriguez-Cubillo were admitted to our institution with COVID-19 between March 15and April, 24,
Email: brcubillo@gmail.com
2020. Mycophenolate and/or mammalian target of rapamycin inhibitors (mTORi)
were discontinued in all patients. Two therapeutic strategies were compared: Group
1, minimization of calcineurin inhibitors (N  =  6); and Group 2, cyclosporine-based
therapy (N  =  23), with 15 patients switched from tacrolimus. Hydroxychloroquine
was considered in both strategies but antivirals in none. Six patients died after res-
piratory distress (20.6%). Five required mechanical ventilation (17.2%), and 3 could
be weaned. Nineteen patients had an uneventful recovery (65.5%). In group 1, 3 of
6 patients died (50%) and 1 of 6 required invasive mechanical ventilation (16.7%). In
group 2, 3 of 23 patients died (12.5%). Renal function did not deteriorate and signs
of rejection were not observed in any patient on the second treatment regime. In
conclusion, immunosuppressant treatment based on cyclosporine could be safe and
effective for KTRs diagnosed with COVID-19.

KEYWORDS

clinical research/practice, health services and outcomes research, kidney transplantation /

nephrology, kidney disease: infectious, immunosuppressant

Abbreviations: ARDS, acute respiratory distress syndrome; COVID-19, coronavirus disease 2019; CsA, cyclosporine; H, hydroxychloroquine; ICU, intensive care unit; IQR, interquartile
range; IST, immunosuppressant treatment; IL-6, interleukin-6; IMV, invasive mechanic ventilation; IG, intravenous immunoglobulin; KT, kidney transplantation; MMF/MPA,
mycophenolate mofetil/mycophenolic acid; mTORi, mammalian target of rapamycin inhibitors; RT-PCR, reverse transcription polymerase chain reaction.; SARS-CoV-2, severe acute
respiratory syndrome coronavirus 2; SpO2/FiO2, pulse oximetry saturation/fraction of inspired oxygen ratio.

© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons

Am J Transplant. 2020;20:3173–3181.  |
amjtransplant.com     3173
 16006143, 2020, 11, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ajt.16141 by Spanish Cochrane National Provision (Ministerio de Sanidad), Wiley Online Library on [19/10/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
|
3174       RODRIGUEZ-CUBILLO et al.

1 |  I NTRO D U C TI O N 2.2 | Patient management

Coronavirus disease 2019 (COVID-19) is a novel viral disease with All KT recipients presenting at the emergency room or outpatient clinic
tens of thousands of infected patients worldwide.1 Clinically, with suggestive symptoms or signs were tested for SARS-CoV-2 in-
when symptomatic, the disease is characterized by fever, cough, fection. The diagnosis of COVID-19 was made by means of real time
lymphopenia, dyspnea, and, eventually, respiratory distress and reverse transcription polymerase chain reaction (RT-PCR) in naso-
multiorgan failure in severe cases.1,2 Mortality in the general pharyngeal swab or sputum samples according to established methods.
population is about 1%-6% but it is higher among patients with
3
previous comorbidities (15%). Recent publications have demon-
strated that the clinical course of this disease among transplanted 2.3 | Therapy approach
patients is more aggressive, with mortality being as high as 14%-
25% 4-8
Besides, renal function also appears to be affected. 4,9 To 2.3.1 | I. Adjustment of immunosuppressive regimen
date, recommendations include the use of antivirals and down-
grading immunosuppressive treatment,10-12 but the evidence Group 1: Minimization of Immunosuppressive Therapy.
10-12
supporting these recommendations is weak. Hypothetically, Following current recommendations we tended to down-
conversion to cyclosporine (CsA) could improve outcomes in grade immunosuppressive therapy; therefore, mycophenolate and/
kidney transplant (KT) patients with COVID-19 as CsA has both or rapamycin were discontinued and the dose of calcineurin inhib-
antiviral power (including with severe acute respiratory syn- itors was reduced.
drome coronavirus [SARS-Cov] species) and immunomodulatory Group-2: Cyclosporine-based immunosuppression therapy.
effect.13 Besides, CsA may help to avoid graft rejection during Given the poor evolution of the first patients with SARS-Cov-2
the infection. treated with standard regimes, our previous experience with CsA in
Therefore, we aimed to describe the initial experience in a refer- other viral infections such as polyomavirus BK nephropathy infec-
ral kidney transplantation center treating renal transplants infected tion, and the theoretical benefits of cyclosporin in COVID-19,13 we
with COVID-19 with cyclosporine. decided to change the strategy of immunosuppressive therapy: we
maintained cyclosporin at low doses when it was part of the patients’
usual treatment, and those on tacrolimus or mammalian target of
2 |  M ATE R I A L S A N D M E TH O DS rapamycin inhibitors (mTORi) were switched to cyclosporin. CSA tar-
get concentration was around 50-100 ng/mL.
2.1 | Study population and design

We included all kidney transplant patients with polymerase chain 2.3.2 | II. Antiviral and immunomodulatory therapy
reaction (PCR)-confirmed SARS-CoV-2 infection who were referred
to our institution (a referral kidney transplantation center) between Both protocols included the use of hydroxychloroquine, 400  mg
March 15 and April 24, 2020. Final follow-up date was May 19, 2020. twice daily orally for the first 24 hours, followed by 200 mg twice
Clinical, laboratory, and radiologic data were collected. All labora- daily for 5-10 days. Antivirals were not administered in any group.
tory and imaging tests were performed as part of standard of care. Moreover, high doses of steroids were used if evidence of pro-
The degree of severity of COVID-19 on admission was determined gressive respiratory, radiologic, or inflammatory profile worsening
by the need for oxygen therapy and the presence of pneumonia in appeared. Our local protocol included a 4-day cycle of methyl-pred-
X-ray. We also considered analytical changes, especially inflamma- nisolone with a recommended dosing of 250-125-125-125 mg. Still,
tory and renal function parameters. Inflammatory parameters in- individual dosing was left up to the attending physician.
cluding PCR, procalcitonin, D dimer, ferritin, lactate dehydrogenase Tocilizumab was added if Il-6 was > 60 pg/mL. Initial local pro-
(LDH), and interleukin-6 (IL-6) of patients were monitored on admis- tocols recommended a first dose of 600 mg or 400 mg (according to
sion and on a daily basis. patient´s weight), followed by 2 other doses of 400  mg. Protocols
Respiratory function was assessed by means of the pulse ox- were subsequently modified and a single dose of 600 mg or 400 mg
imetry saturation/fraction of inspired oxygen (SpO2/FiO2) ratio, according to weight was recommended. Patients with IgG < 700 mg/
which has a good correlation with the partial pressure of arte- dl received an intravenous immunoglobulin (IG) cycle (10 g/kg).
rial oxygen (PaO2)/FiO2 ratio (SpO2/FiO2  =  64 + 0.84 x PaO2/
FiO2).14
Unfavorable outcome was defined by the presence of progres- 2.3.3 | III. Other coadjuvant therapies
sive respiratory failure; ie sustained worsening of the SpO2/FiO2
ratio and/or development of acute respiratory distress syndrome Antibiotics were prescribed if bacterial superinfection was sus-
(ARDS) resulting in need of intensive care unit (ICU) admission and/ pected. Ceftriaxone was the preferred antibiotic but was modified
or death. based according to antibiograms.
 TA B L E 1   Baseline and on admission characteristics

Baseline characteristics Admission features

Patient. (Admission Gender /Age Transplantation date (n Cardiovascular risk Day of symptoms Oxygen Renal function CKD-
date) (years) previous transplant) factors when admission X-ray Requirement EPI mL/min (AKI)

Group 1 P 1 (03.13.2020) F (74) 2005 (1) HBP, DL, OB, DM 2 (F*) BPS None 80.0 (No)
P 2 (03.16.2020) M (50) 2003 (1) HBP, DL 4 (F*, M*) No infiltrates None 36.0 (No)
RODRIGUEZ-CUBILLO et al.

P 3 (03.17.2020) M (71) 2012 (2) HBP, DL 4 (F*, C, M*, D) No infiltrates None 15.0 (No)
P 5 (03.17.2020) F (66) 2008 (1) DL, OB 7 (F*, C, M*, D, Dy) LPS NG 21.0 (Yes)
P 6 (03.17.2020) F (66) 2011 (1) HBP, OB 0 (CF) No infiltrates None 80.0 (No)
P 7 (03.19.2020) F (63) 2018 (1) HBP, DL, OB 4 (M*, Dy) No infiltrates None 44.0 (No)
Group 2 P 4 (03.17.2020) M (66) 2014 (1) HBP, DL 8 (F*, C, M*, Dy) No infiltrates None 27.7 (No)
P 8 (03.19.2020) M (75) 2006 (1) HBP, DL 0 (CF) No infiltrates None 46.0 (No)
P 9 (03.25.2020) M (71) 2009 (1) HBP, DL, OB, DM 12 (F*, C, M*, Dy) LPS NG 33.0 (Yes)
P 10 (03.26.2020) M (68) 2006 (1) HBP, DL, DM 1 (F*, C, M*, D, Dy) BPS NG 93.0 (No)
P 11 (03.27.2020) M (45) 2005 (1) HBP, DL 4 (F*, M*, D, Dy) BPS VM 11.0 (Yes)
P 12 (03.27.2020) M (63) 2020 (1) HBP, DL, DM 7 (F*, C, M*, D, Dy) BPS VM 11.9 (Yes)
P 13 (03.27.2020) M (79) 2006 (1) HBP, DM 30 (F*, C, M*, D, Dy) No infiltrates None 16.0 (Yes)
P 14 (03.30.2020) M (28) 2012 (1) HBP, DL 10 (F*, C, M*, D) LPS None 30.0 (Yes)
P 15 (03.31.2020) F (48) 2001 (1) HBP, DL, OB 7 (F*, C, M*) BPS None 91.6 (No)
P 16 (04.01.2020) F (38) 2015 (4) HBP, DL 7 (F*, M*, Dy) LPS None 17.0 (Yes)
P 17 (04.02.2020) M (69) 2018 (1) HBP, DL, OB 7 (F*, C, T, M*) LPS None 48.0 (Yes)
P 18 (04.02.2020) M (63) 2011 (1) HBP, DL, OB, DM 5 (F*, C, D, Dy) LPS None 30.0 (Yes)
P 19 (04.04.2020) F (69) 2019 (1) HBP, DL, OB, DM 0 (CF) LPS None 13.0 (Yes)
P 20 (04.06.2020) M (63) 2019 (1) HBP, OB, DM 5 (F*, C, D) BPS None 9.40 (No)
P 21 (04.06.2020) F (56) 2006 (1) HBP, DL, OB 7 (C, M*, D) LPS None 43.5 (No)
P 22 (04.06.2020) M (63) 2018(2) HBP, DL, OB, DM 3 (M*, Dy) BPS VM 8.0 (Yes)
P 23 (04.06.2020) M (43) 2013 (1) HBP, DL, OB, DM 7 (F*, C, D) BPS None 21.3 (Yes)
P 24 (04.07.2020) M (73) 2019 (1) HBP, DL, OB, DM 10 (F*, M*) No infiltrates None 25.0 (No)
P 25 (04.09.2020) M (65) 2010 (1) HBP 1 (F*, M*, D) No infiltrates None 19.0 (Yes)
P 26 (04.10.2020) M (80) 2007 (1) HBP, DL, OB 3 (F*, C, Dy), BPS NG 25.0 (No)
P 27 (04.14.2020) F (80) 2018(1) HBP, DL. OB 6 (M*) No infiltrates None 31.7 (No)
P 28 (04.14.2020) F (64) 2019 (1) HPB, DL 2 (C, D, Dy) No infiltrates None 71.6 (No)
P 29 (04.24.2020) F (78) 2000 (1) HBP, DL, 3 (M*, C, D, Dy) LPS None 20.7 (Yes)
|

Abbreviations: AKI, acute kidney injury; BPS, bilateral patchy shadowing; C, cough; CF, casual findings of pulmonary infiltrates in computed tomography; CKD-EPI, Chronic Kidney Disease Epidemiology
Collaboration; D, diarrhea; DL, dyslipidemia; DM, diabetes mellitus; Dy, dyspnea; F*= fever; F, female; HBP, hyper blood pressure; LPS, local patchy shadowing; M*= myalgias; M, male; NG, nasal glasses
      3175

(2-3 lpm); OB, obesity; VM, venturi mask (8-10 lpm).

16006143, 2020, 11, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ajt.16141 by Spanish Cochrane National Provision (Ministerio de Sanidad), Wiley Online Library on [19/10/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
 16006143, 2020, 11, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ajt.16141 by Spanish Cochrane National Provision (Ministerio de Sanidad), Wiley Online Library on [19/10/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
|
3176       RODRIGUEZ-CUBILLO et al.

In addition, we prescribed anticoagulant drugs in patients with 69%), myalgia (n = 21, 72.4%), cough (n = 17, 58.6%), dyspnea (n = 14,
D dimer above 3000 ng/mL. Our local protocols included enoxapa- 48.3%), and diarrhea (n = 14, 48.3%) (Table 1).
rin or tinzaparin at prophylactic doses, adjusted at weight and renal On admission, only 7 patients (24.1%) required supplemental ox-
function.15 ygen therapy (Table 1), though 18 finally received it throughout the
hospitalization (62%) (Table 3). Among them, 9 cases had high PaO2/
FiO2 ratio (31%) (Table 3).
2.4 | Statistical analysis We did not detect any statistically significant baseline clinical
difference between the two groups.
Categorical variables were expressed with absolute/relative fre- Inflammatory parameters are shown in Table 2 and Table 4.
quency and quantitative with median and interquartile rank, and Patients with poor prognosis (death or invasive mechanical ventila-
were compared with nonparametric test according to their distri- tion requirement) had higher inflammatory parameters and peak lev-
bution. Statistical analysis was performed with SPSS (IBM Corp. els tended to be later on the course of the disease (P < .05) (Table 2).
Released 2017. IBM SPSS Statistics for Windows, Version 25.0. IBM Initially, the most common pattern on chest X-ray was bilateral
Corp., Armonk, NY) (n  =  9, 31%) and local (n  =  9, 31%) patchy shadowing. Initial imag-
ing tests were normal in 11 patients (37.9%) (Group = 1 4 patients,
66.75% and Group = 2 7 patients, 29.2%). Nineteen patients (65%)
3 |   R E S U LT S suffered a radiological worsening during the hospitalization (Table 3).
Fourteen patients (48.2%) presented with acute kidney injury
Patients´ characteristics and pathological features on admission are on admission (Table 1). Ten patients recovered their baseline renal
summarized in Table 1. Tables 2 and Table 3 show the clinical, ra- function at the end of follow-up (71.4%%). The 4 patients who did
diologic, and analytical evolution during the in hospital stay. Table 4 not recover baseline renal function died. Three of them needed
summarizes the differences between the group of patients with min- renal replacement therapy in the first days of admission (10.3%) be-
imization of immunosuppression (Group 1, n = 6) and the group of cause these patients already had a baseline Chronic Kidney Disease
patients who were being already treated with cyclosporine or con- Epidemiology Collaboration (CKD-EPI) < 15 mL/min (Table 3). These
verted from previous immunosuppressants to cyclosporine (group 2, patients belonged to Group 2. We have not observed any episode
n = 23). All patients were followed until May 19, 2020. Median time suggestive of acute rejection in any group of patients.
of follow-up was 43 days (interquartile range [IQR] 35-54 days). Baseline characteristics and admission features of both groups are
Twenty-six patients (89.65%) were symptomatic on admission summarized in Table 4. Given the small sample size we cannot draw
and the median time from the onset of symptoms to admission was any robust conclusion regarding differences between the groups, but
of 5 days (IQR 2.5-7). Most common symptoms were fever (n = 20, patients in Group 2 appear to be more seriously affected (Table 4).

TA B L E 2   Inflammatory parameters evolution

Total (n = 29) Median, Unfavorable evolution Favorable evolution

(IQR) (n = 9) Median, (IQR) (n = 20) Median (IQR) P

RCP On admission 3.01 (0.6-9.8) 6.46 (2.26-14.8) 2.59 (0.3-7.32) .153

Max levels 8.3 (1.9-12.7) 12.3 (8-25.5) 4.15 (1.34-10.12) .017
Max levels day 3 (1-8) 7 (2.25-11.75) 2 (1-5) .065
PCT On admission 0.16 (0.07-0.70) 0.32 (0.16-2.63) 0.12 (0.07-0.49) .066
Max levels 0.22 (0.1-1.04) 1.37 (0.32-20.63) 0.12 (0.08-0.42) .005
Max levels (day) 3 (1-5) 6 (2.25-11.75) 1 (1-3) .019
D dimer On admission 1429 (754-2358) 2001 (967-9315) 1333 (585-2235) .238
Max levels 1926 (1620-5249) 5691 (3273-20020) 1749 (1427-2275) .003
Max levels(day) 6.0 (1.3-11.7) 10.5 (5.5-14.0) 1.5 (1-8) .019
Ferritin On admission 647 (348-1642) 597 (478-1986) 698 (285-1678) .562
Max levels 1226(496-2027) 1698 (1392-2441) 884 (350-1981) .039
Max levels day 7 (1.5-9.5) 11 (5.75-12) 3 (1-8) .009
LDH On admission 488 (360-712) 719 (434-789) 462 (330-606) .043
Max levels 713 (457-981) 1154 (897-1353) 549 (443-729) .001
Max levels day 8 (3.0-12.0) 11.5 (8.5-12) 4 (1-10) .047
IL-6 Max levels 62.0 (13.3-122.7) 115 (77.2-168.25) 37 (14.4-107.75) .047
 16006143, 2020, 11, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ajt.16141 by Spanish Cochrane National Provision (Ministerio de Sanidad), Wiley Online Library on [19/10/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
RODRIGUEZ-CUBILLO et al. |
      3177

4-8
Regarding immunosuppressive therapy approach, most patients Recently published reports suggest that SARS-CoV-2 infec-
were previously treated with sodium mycophenolate (N = 22, 75.8%), tion may have a more severe course in KTRs and different clinical
tacrolimus (N = 19, 65.5%), and low doses of steroids (N = 23, 79.3%) presentation as compared to general population. We found, accord-
(Table 3). Mycophenolate and/or rapamycin were discontinued in all ingly with previous reports, that gastrointestinal symptoms and my-
patients and the dose of tacrolimus was reduced in the first patients. algias were more frequent in KTR (48.3%). Dyspnea, which has been
2,8
Initial strategy with the first patients showed poor outcomes associated with a poor prognosis was also very common among
(see Table 3). However, we observed an acceptable infection course our patients (48.3%).
in one of those patients (patient p4), who was previously on cyc- SARS-CoV-2 mortality is around 2.3% in healthy population, but
losporine (p4). In the management of patients with viral infections, it is higher in patients with preexisting comorbidities (5.6%-10.5%).3
such as polyomavirus BK nephropathy, our unit had good outcomes KTRs are in this group of patients, as they usually have a higher prev-
with the switch to cyclosporine from tacrolimus. In addition, it has alence of comorbidities, which largely increase mortality by them-
been suggested that CsA could be beneficial in the treatment of selves. Data on mortality due to SARS-Cov-2 among KTRs is limited,
SARS-CoV infection.13 For all these reasons, we decided to modify and it has been reported to rank between 13% and 27.8%. 5-9 Global
our therapeutic strategy and prescribe cyclosporine systematically. mortality in our patients was 20.7% (6/29), but among patients who
In the overall cohort, 23 patients (79.3%) received cyclosporine had received cyclosporine as immunosuppressant treatment, it was
and prednisone during the infection. Six were already treated with 13% (3 patients out of 23), Nevertheless, it is difficult to draw robust
cyclosporine prior to SARS-CoV-2 infection, and 19 patients (65.5%) conclusions from these studies given the small sample size.
16
were switched from their usual immunosuppressive therapy to this According to Siddiqi et al, SARS-Cov-2 disease shows up in
combination. Fifteen patients were switched to CsA from tacrolimus three stages: Stage I, early infection; II, pulmonary involvement; and
(Table 3). At the moment of submission of this manuscript, 14 pa- III, systemic hyperinflammation. The last stage, which has the poorest
tients (48.2%) were kept on treatment with cyclosporine. Median outcomes, might be associated with a hyperinflammatory state or cy-
levels of cyclosporine during hospitalization were 60  ng/mL (IQR tokine-release syndrome.13,16 Therefore, a comprehensive approach to
40-82.50  ng/mL). In general, doses of CsA were lower during the clinical phenotyping has to be done to distinguish the phase where the
treatment with hydroxychloroquine (median 50 mg/24 h), compared viral pathogenicity is dominant and the moment when the host inflam-
with doses after discontinuation (median 150 mg/24 h). matory response becomes predominant. Hence, antivirals proposed
Regarding SARS-CoV-2 specific treatment, all patients except 2 to SARS-Cov-2 treatment,17 could be more useful at the first stage,
received hydroxychloroquine and all of them received antibiotics. when viral replication is more important. Therapy in phase III might in-
(Table 3 and Table 4). clude the use of immunomodulators to reduce systemic inflammation,
We used early administration of high-dose of steroids in 18 pa- such as steroids, tocilizumab or anakinra, and immunoglobulins.13,16-18
tients (62.1%) and tocilizumab in 9 (31%). Also, 8 patients received Cyclosporine could also be considered in this stage.13,16-18
immunoglobulins (27.6%). Twenty-four patients were treated with Lopinavir/ritonavir in combination with hydroxychloroquine is
anticoagulants at prophylactic doses (82.75%). (Table 3 and Table 4). widely used to reduce the viral replication.10-12 However, a recent trial
Table 4 summarizes principal outcomes. At this point, 6 patients comparing lopinavir/ritonavir vs. placebo found no significant benefits
had died because of ARDS (20.7%). Five patients (17.2%) required in terms of viral clearance and survival between the two arms.19 It is
mechanical ventilation at some point of the progression of the dis- important to note that most of the patients included in the trial (just as
ease but 3 of them were weaned and transferred to the hospitaliza- our series) were admitted in an advanced stage of the disease with a
tion ward and then discharged. In total, 23 patients (79.3%) had a significant inflammatory status. At that point, patients probably would
favorable evolution and were discharged. have benefited not from antiviral treatments but from an inflammation
Mortality was higher in immunosuppression minimization strat- targeted approach.18 Furthermore, the utility of lopinavir/ritonavir in
egy group as compares to cyclosporine strategy group: 3/6 (50%) Vs. transplanted patients could be limited given their interactions with
3/23 (13%), respectively (Table 4). calcineurin inhibitors 7 and the risk of QTc prolongation. Both side ef-
fects are boosted if combined with hydroxychloroquine.
It is possible that conversion to cyclosporine might be an option
4 | D I S CU S S I O N in the SARS-CoV-2 management in KTRs. First, CsA could have an
antiviral effect in patient with coronavirus infection. CsA is a well-
There is a dearth of information about the impact of the COVID-19 known immunosuppressive drug that binds to cellular cyclophilins
infection on kidney transplant recipients (KTRs). Little is known about to inhibit calcineurin. The inhibition of calcineurin blocks the tran-
optimal treatment for these patients. Current recommendations scription of genes encoding cytokines such as interleukin-2. This ef-
include the use of antivirals and minimization of immunosuppres- fect is useful as immunomodulator and immunosuppressant agent in
10-12
sion. We aimed to report our experience treating 29 transplanted kidney transplant recipients. Interestingly, many viruses require cy-
COVID-19 patients, 23 of whom had their immunosuppressive treat- clophilins for replication, including the coronavirus, so cyclosporine
ment strategy based on cyclosporine. To date there is no other report could suppress its replication. 20 In vitro investigations have demon-
describing experience in renal transplant patients using this strategy. strated an early block in SARS-CoV replication associated to CsA. 21
 TA B L E 3   Treatment and evolution
|

Treatment Evolution
3178      

Change to Oxygen
Initial CsA (day Renal function X-ray requirement (on
change on from Other TZ (day/oxygen/ (hemodialysis day worsening set/max/end Actual
Patients Onset IST IST admission) treatments doses) Anti-C from admission) (day) follow-up) status

Group1 P1 FK + MPA Low dose No H, IG No No Stable Yes (5), BPS None/R Death
FK
P2 FK + MPA Low dose Yes (24) H, STB, TZ Yes (8/R) (1200mg) Yes Stable Yes (8), BPS None/IMV/None ICU/
FK Discharge
P3 FK + RAPA+P P Yes (15) H, STB, TZ Yes (8/ Yes Stable Yes (8), BPS None/None Discharge
None) (1200 mg)
P5 EV + MPA+P P No IG No No AKI no recovered Yes (5), BPS NG/R Death
P6 P P No H, STB No Yes Stable Yes (12), BPS None/VM Death
P7 FK + MPA+P Low dose No H, IG No No Stable No None/NG/None Discharge
FK
Group 2 P4 CsA + MPA+ P CsA + P Previously H, IG No No Stable Yes (7), LPS None/None Discharge
P8 RAPA + MPA+P CsA + P Yes (7) H No Yes Stable Yes (7), LPS None/None Discharge
P9 FK + RAPA CsA + P Yes (3) H, STB No Yes AKI recovered Yes (9), BPS NG/NG/None Discharge
P 10 FK + MPA+P CsA + P Yes (5) H, STB, TZ Yes (8/R) (600 mg) Yes Stable No NG/IMV/None ICU/
Discharge
P 11 CsA + MPA+P CsA + P Previously H, STB, TZ Yes (2/R) (600 mg) Yes HD (1) Yes (5), BPS VM/IMV ICU/ Death
P 12 FK + MPA+P CsA + P Yes (3) H, IG, STB, Yes (2/ Yes HD (3) Yes (16), BPS VM/IMV ICU/ Death
TZ VM) (600 mg)
P 13 CsA + AZA+P CsA + P Previously H, STB No Yes AKI recovered Yes (7), LPS None/NG/None Discharge
P 14 EV + MPA+P CsA + P Yes (1) H No Yes AKI recovered No None/None Discharge
P 15 FK + RAPA CsA + P Yes (1) H, STB No Yes Stable Yes (6), BPS None/NG/None Discharge
P 16 FK + RAPA+P CsA + P Yes (1) H, STB, TZ Yes (4/R) (400 mg) Yes AKI recovered Yes (4), BPS None/IMV/None ICU/
Discharge
P 17 FK + MPA+P CsA + P Yes (1) H, STB No Yes AKI recovered Yes (6), BPS None/NG/None Discharge
P 18 FK + MPA+P CsA + P Yes (1) H, STB, TZ Yes (1/ Yes AKI recovered No None/None Discharge
None) (600 mg)
P 19 FK + MPA+P CsA + P Yes (1) H, IG No Yes AKI recovered Yes (2), LPS None/None Discharge
P 20 FK + MPA+P CsA + P Yes (1) H, IG, STB, Yes (1/ Yes Stable Yes (2), BPS None/NG/None Discharge
TZ NG) (600 mg)
P 21 FK + MPA+P CsA + P Yes (1) H, STB, TZ Yes (5/ Yes Stable Yes (5), LPS None/None Discharge
None) (600 mg)
RODRIGUEZ-CUBILLO et al.

(Continues)

16006143, 2020, 11, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ajt.16141 by Spanish Cochrane National Provision (Ministerio de Sanidad), Wiley Online Library on [19/10/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
 16006143, 2020, 11, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ajt.16141 by Spanish Cochrane National Provision (Ministerio de Sanidad), Wiley Online Library on [19/10/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
RODRIGUEZ-CUBILLO et al. |
      3179

Moreover, it has been suggested that cyclosporine could slow down

the replication of other viruses such as human immunodeficiency

Discharge
Discharge
Discharge
Discharge
Discharge
Discharge
Discharge
Actual
virus type 1 (HIV-1),13 hepatitis C virus,13 and polyoma BK virus. 22

status

Death
There is limited evidence of antiviral effect of CsA in vivo, but it
has been suggested that switching from tacrolimus to low-dose CsA
may be an effective therapy for BK virus nephropathy. 23 However,

None/NG/None

None/NG/None
requirement (on
set/max/end the evidence for in vitro CsA associated antiviral effects are lim-

None/None
None/None

None/None

None/None
follow-up)

VM/CPAP
ited, and other effects (eg, less immunosuppressive power, reduced

NG/None
Oxygen

mycophenolic acid exposure in CsA-treated patients) may be likely

contributors to the observed effects in clinics more than any direct
antiviral effects. Second, cyclosporine has also been used to suc-
cessfully treat hemophagocytic lymphohistiocytosis (HLH) and to
Yes (4), BPS

Yes (6) BPS

worsening

inhibit nuclear factor of activated T cell–mediated IL-2 gene tran-

X-ray

(day)

scription, reducing cell proliferation and the concomitant produc-

No
No
No
No
No

No
tion of other cytokines.13 Given that SARS-CoV-2 is associated with
cytokine-release syndrome, cyclosporine might be helpful in the hy-
perinflammatory phase of SARS-CoV-2 infection.13 Indeed, CsA has
(hemodialysis day
from admission)
Renal function

AKI recovered

AKI recovered

AKI recovered

been suggested to be beneficial in other SARS-Cov-2 manifestations,

such as inflammatory intestinal lesions. 24 Finally, cyclosporine may
HD (2)

Stable

Stable
Stable
Stable

help to avoid graft rejection during the infection. Although an anti-

viral effect has also been reported for other immunosuppressants
Evolution

such as mTORi, 25 their lung side effects 26

could make these drugs
Anti-C

less suitable. For all these reasons, we believe that cyclosporine is

Yes
Yes

Yes
Yes
Yes
Yes
Yes
No

useful in KTR with SARS-CoV-2. Our clinical observations support

this hypothesis given that the mortality was lower in the group of
TZ (day/oxygen/

patients treated with CsA, (50% vs 13%, P = .047). Moreover, the

analytical worsening (43.5% vs 100%, P = .017) and oxygen-therapy
requirements (basal: 16.1% vs 43.5%, P = .037) were also lower in
doses)

this group. However, it is difficult to draw robust conclusions be-

No
No
No
No
No
No
No
No

cause of the small size of sample.

The role of high-dose steroids in this disease remains controversial,
treatments

because their use within the first phase could delay viral clearance.27
H, STD
H, STB
H, STB
Other

H, IG

However, in patients with an inflammatory status due to SARS-Cov-2

STB
H
H

infection, corticoids might be beneficial.28 Small series have reported

admission)

Previously

Previously

Previously

a lower mortality in patients treated with steroids as compared with

Change to
CsA (day

5
those who were not (13% vs 25%). These findings are inconclusive
Yes (1)

Yes (1)
Yes (1)
Yes (1)
Yes (1)
from

due to the limited sample sizes. We added low-dose prednisone as a

coadjuvant immunosuppressor to cyclosporine in 4 patients who had
change on

not taken it previously, and boluses were administered in 18 patients

CsA + P
CsA + P
CsA + P
CsA + P
CsA + P
CsA + P
CsA + P
CsA + P
Initial

(62.1%) to try to control the aberrant immune response secondary to

IST

SARS-CoV-2. Other investigators have used high doses of steroids 5,6

but in a lower proportion of patients as compared with our series.
29
Tocilizumab and immunoglobulins were also used with the
CsA + MPA+P

CsA + MPA+P

FK + RAPA+P

30
Some authors 4-8 also used this IL-6 inhibitor in KTR
FK + MPA+P

FK + MPA+P

FK + MPA+P

same purpose.
CsA + MPA
FK + MPA
Onset IST

with fairly good outcomes. According to recent investigations,18 we

tried to prescribe tocilizumab early when indicated, as the later it is
TA B L E 3   (Continued)

given the poorer its effect could be. Immunoglobulins have also been
used in renal transplanted patients.6 They could have some utility,
P 22

P 25
P 23

P 29
P 28
P 26
P 27
P 24

as they could modulate the immune system during the hyperinflam-

matory phase.13,17,18 Finally, taking into account the prothrombotic
Treatment

state of this disease,15 we added anticoagulant treatment in selected

Patients

6
patients. Akakin et al described the use of apixaban, but it is not
used in other series.5-8
 16006143, 2020, 11, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ajt.16141 by Spanish Cochrane National Provision (Ministerio de Sanidad), Wiley Online Library on [19/10/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
|
3180       RODRIGUEZ-CUBILLO et al.

TA B L E 4   Features admission and outcomes by immunosuppression strategy

Baseline characteristics Total N = 29 Minimization N = 6 Cyclosporin N = 23 P

Age, m (IQR) 66 (59-72) 66 (59-71) 65 (56-73) .845

Female Gender, n (%) 12 (41.4) 4 (66.7) 8 (34.8) .198
Transplantation time mo., m(IQR) 99.22 (26-171) 99 (26.6-159) 102 (27.14-171) .862
Risk factors > 3, n (%) 18 (62.1) 2 (33.3) 16 (69.6) .164
Admission characteristics
Symptoms days, m (IQR) 5 (2.5-7) 4 (1.5-4.75) 6 (3-7) .192
Dyspnea, n (%) 12 (44.4) 2 (33.3) 13 (52.2) .361
X-ray abnormalities No infiltrates, (%) 11 (37.9) 4 (66.75) 7 (29.2) .344
BPS, n (%) 9 (31) 1 (16.7) 8 (34.8)
Oxygen requirement Basal n, (%) 22 (75.9) 5 (83.3) 17 (73) .642
VM/R/CPAP n, (%) 3 (10.3) 0 (0) 3 (13)
D dimer (ng/mL), m (IQR) 1429 (754-2358) 1066 (844-1042) 1627 (602-2691) .146
Ferritin (ng/mL), m (IQR) 647 (348-1682) 554 (67-2764) 725(403-1684) .380
LDH, IU/l, m (IQR) 488 (360-712) 443 (399-535) 584 (330-719) .742
CKD-EPI, mL/min, m (IQR) 25.0 (16.75-45) 41. (19-80.5) 25 (16.43) .212
AKI, n (%) 14 (48.2) 1 (16.7) 13 (56.5) .169
Treatments
Hydroxychloroquine 27 (93.1) 5 (83.3) 22 (95.7) .377
Steroids bolus, n (%) 18 (62.1) 3 (50) 15 (62.5) .646
Cumulative steroid doses, mg, m (IQR) 735 (375-1260) 1033 (125-1250) 735 (375-1455) 1.000
Tocilizumab, n (%) 9 (31) 2 (33.3) 7 (30.4) 1.000
IG, n (%) 8 (27.6) 3 (50) 5 (21.5) .300
Anticoagulation, n (%) 24 (82.2) 3 (50) 21 (91.3) .046
Outcomes
Radiologic worsening, n (%) 19 (65.5) 5 (83) 14 (60.9) .633
Analytical worsening, n (%) 16 (55.2) 6 (100) 10 (43.5) .017
Ferritin max, ng/mL, m (IQR) 1226 (496-2027) 2090 (1190-3482) 923 (443-1887) .140
LDH max, IU/l m (IQR) 713(457-981) 1167 (768-1466) 645 (448-829) .021
AKI recovered, n (%) 10 (34.48) 0 (0) 10 (43.4) .145
AKI with HD, n (%) 3 (10.3) 0(0) 3 (13) .145
Oxygen requirement increase Yes, n (%) 16 (55.2) 5 (83.3) 11 (47.8) .119
Day, m (IQR) 4 (2-7) 8 (3.5-5) 3.5 (5.5-10) .006
Max oxygen requirement Basal, n (%) 11 (37.9) 1 (16.7) 10 (43.5) .035
NG, n (%) 9 (31) 1 (16.7) 8 (34.8)
IMV, n (%) 5 (17.2) 1 (16.7) 4 (17.4) 1.000
Death, n (%) 6 (20.7) 3 (50) 3 (13) .047
Discharge, n (%) 23 (79.3) 3 (50) 20 (87)

Abbreviations: AKI, acute kidney injury; BPS, bilateral patchy shadowing; max, maximum; CKD-EPI, Chronic Kidney Disease Epidemiology
Collaboration; CPAP, continuous positive airway pressure; HD, hemodialysis, IG, immunoglobulins; IMV, invasive mechanical ventilation; IQR,
interquartile range; m, median; NG, nasal glasses (2-3 lpm); R, reservoir (15 lpm); VM, venturimask (8-10 lpm).
Actual status (May 19, 2020), Units: D dimer (ng/mL): normal range < 500 ng/mL, ferritin (ng/mL) normal range 30-350 ng/mL, LDH, lactate
dehydrogenase (UL/l), normal range 240-480 U/ I. Day, day of oxygen requirement increase from admission.

5 |  CO N C LU S I O N S to identify the stage of the disease and prescribe specific
treatment.
Given that SARS-CoV-2 infection has two principal phases— Among KTRs the immune system is altered by the immunosup-
a purely viral infection and an inflammatory process with dif- pressive medication, and the balance between control of infection
ferent prognostic and therapeutic implications—it is relevant and inflammation can be even more complex.
 16006143, 2020, 11, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ajt.16141 by Spanish Cochrane National Provision (Ministerio de Sanidad), Wiley Online Library on [19/10/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
RODRIGUEZ-CUBILLO et al. |
      3181

Cyclosporine can be useful at any moment during the course of 14. Rice TW, Wheeler AP, Bernard GR, et al. Comparison of the SpO2/
FiO2 ratio and the PaO2/FiO2 ratio in patients with acute lung in-
the disease given its effect on the inhibition of viral replication, main-
jury or ARDS. Chest. 2007;132(2):410-417.
tenance of kidney graft and down regulation of the immune response. 15. Bikdeli B, Madhavan MV, Jimenez D, et al. COVID-19 and tthrom-
Other adjuvant therapies may include the use of tocilizumab, botic or thromboembolic disease: implications for preven-
high-dose steroids, immunoglobulins and anticoagulation treatment. tion, antithrombotic therapy, and follow-up. J Am Coll Cardiol.
2020;S0735–1097(20):35008-7.
Our current treatment protocol appears to be associated with
16. Siddiqi HK, Mehra MR. COVID-19 illness in native and immunosup-
favorable outcomes, but longer follow-up of a larger cohort of pa- pressed states: a clinical-therapeutic staging proposal. J of Heart
tients is needed. and Lung Transplant. 2020;39(5):405-407.
17. Sanders JM, Monogue ML, Jodlowski TZ, Cutrell JB. Pharmacologic
D I S C LO S U R E treatments for coronavirus disease 2019 (COVID-19) a review [pub-
lished online ahead of print 2020]. JAMA. 2020.
The authors of this manuscript have no conflicts of interest to dis-
18. Mehta P, McAuley DF, Brown M, et al. COVID-19: consider
close as described by the American Journal of Transplantation. cytokine storm syndromes and immunosuppression. Lancet.
2020;395:1033-1034.
DATA AVA I L A B I L I T Y S TAT E M E N T 19. Cao B, Wang Y, Wen D, et al. A trial of lopinavir-ritonavir
in adults hospitalized with severe COVID-19. N Engl J Med.
No data are available.
2020;382(19):1787-1799.
20. Tanaka Y, Sato Y, Sasaki T. Suppression of coronavirus replication
ORCID by cyclophilin inhibitors. suppression of coronavirus replication by
Beatriz Rodriguez-Cubillo  https://orcid.org/0000-0002-8272-0356 cyclophilin inhibitors. Viruses. 2013;5(5):1250-1260.
21. Wilde AH, Zevenhoven-Dobbe JC, van der Meer Y, et al. Cyclosporin
Natividad C. Romero  https://orcid.org/0000-0003-4031-4816
A inhibits the replication of diverse coronaviruses. J Gen Virol.
2011;92(Pt11):2542-2548.
REFERENCES 22. Li YJ, Weng CH, Lai WC, et al. A suppressive effect of cyclosporine
1. Wang W, Tang J, Wei F, et al. Updated understanding of the out- A on replication and noncoding control region activation of poly-
break of 2019 novel coronavirus (2019-nCoV) in Wuhan. China J omavirus BK virus. Transplantation. 2010;89(3):299-306.
Med Virol. 2020;92(4):441-447. 23. Chen X, Li J, Deng RH, et al. The therapeutic effect of switching from
2. Guan W-J, Ni Z-Y, Hu Y, et al. Clinical characteristics of coronavirus tacrolimus to low-dose cyclosporine a in renal transplant recipients
disease 2019 in China. N Engl J Med. 2020;382(18):1708-1720. with bk virus nephropathy. Biosci Rep. 2019;39(2):BSR20182058.
3. Sun P, Lu X, Xu C, et al. Understanding of COVID-19 based on cur- 24. Rosen MH, Axelrad J, Hudesman D, et al. Management of acute
rent evidence. J Med Virol. 202092(6):548-551. severe ulcerative colitis in a pregnant woman with COVID-19 infec-
4. Coates PT, Wong G, Drueke T, et al. Early experience with COVID- tion: a case report and review of the literature. Inflamm Bowel Dis.
19 in kidney transplantation. Kidney Int. 2020;97(6):1074-1075. 2020;izaa109.
5. Pereira MR, Mohan S, Cohen DJ, et al. COVID-19 in solid organ 25. Bowman LJ, Brueckner AJ, Doligalski CT. The role of mTOR
transplant recipients: initial report from the US epicenter [pub- inhibitors in the management of viral infections: a review
lished online ahead of print 2020]. Am J Transplant. 2020. of current literature. Transplantation. 2018;102(2S Suppl 1):
6. Akalin E, Azzi Y, Bartash R, et al. Covid-19 and kidney transplanta- S50-S59.
tion [published online ahead of print 2020]. N Engl J Med. 2020. 26. Morelon E, Stern M, Israël-Biet D, et al. Characteristics of sirolim-
7. Fernández-Ruiz M, Andrés A, Loinaz C, et al. COVID-19 in solid us-associated interstitial pneumonitis in renal transplant patients.
organ transplant recipients: a single-center case series from Spain Transplantation. 2001;75(2):787-790.
[published online ahead of print 2020]. Am J Transplant. 2020. 27. Lee N, Allen Chan KC, Hui DS, et al. Effects of early corticosteroid
8. Husain SA, Chang JH, Early CDJ, et al. Description of coronavirus treatment on plasma SARS-associated coronavirus RNA concentra-
2019 disease in kidney transplant recipients in New York [published tions in adult patients. J Clin Virol. 2004;31(4):304-309.
online ahead of print 2020]. J Am Soc Nephrol. 2020. 28. Villar J, Ferrando C, Martínez D, et al. Dexamethasone treat-
9. Zhang H, Chen Y, Yuan Q, et al. Identification of kidney transplant ment for the acute respiratory distress syndrome: a multi-
recipients with coronavirus disease 2019 [published online ahead centre, randomised controlled trial. Lancet Respir Med. 2020;8(3):
of print 2020]. Eur Urol. 2020. 267-276.
10. López V, Vázquez T, Alonso-Titos J, et al. Recommendations on 29. Xu X, Han M, Li T, et al. Effective treatment of severe
management of the SARS-CoV-2 coronavirus pandemic (Covid-19) COVID-19 patients with tocilizumab. Proc Natl Acad Sci USA.
in kidney transplant patients [published online ahead of print 2020]. 2020;117(20):10970-10975.
Nefrologia. 2020. 3 0. CaoW LX, Bai T, Fan H, et al. High-dose intravenous immunoglobu-
11. Guidance on the management of transplant recipients diagnosed lin as a therapeutic option for deteriorating patients with coronavi-
with or suspected of having covid 19. British Transplant Society. rus disease Open Forum. Infect Dis. 2020;7(3):ofaa102.
Update 24th April 2020. https://bts.org.uk/wp-conte​nt/uploa​
ds/2020/04/Clini​cal-manag​ement​-of-trans​plant​s-and-immun​osupp​
ressi​on-updat​ed-24th-April​-FINAL.pdf. Accessed May 23, 2020 How to cite this article: Rodriguez-Cubillo B, de la Higuera
12. Alberici F, Delbarba E, Manenti CH, et al. Management of patients
MAM, Lucena R, et al. Should cyclosporine be useful in renal
on dialysis and with kidney transplant during SARS-COV-2 (COVID-
19) pandemic in Brescia. Italy. Kidney Int Rep. 2020;5(5):580-585. transplant recipients affected by SARS-CoV-2?. Am J
13. Willicombe M, Thomas D, McAdoo S. COVID-19 and calci- Transplant. 2020;20:3173–3181. https://doi.org/10.1111/
neurin inhibitors: should they get left out in the storm? JANS. ajt.16141
2020;31(6):1145-1146.