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A single center observational study of the clinical characteristics and short-term outcome of 20 kidney transplant patients admitted for SARS-CoV2 pneumonia.

Identifieur interne : 000996 ( Pmc/Corpus ); précédent : 000995; suivant : 000997

A single center observational study of the clinical characteristics and short-term outcome of 20 kidney transplant patients admitted for SARS-CoV2 pneumonia.

Auteurs : Federico Alberici ; Elisa Delbarba ; Chiara Manenti ; Laura Econimo ; Francesca Valerio ; Alessandra Pola ; Camilla Maffei ; Stefano Possenti ; Nicole Zambetti ; Marianna Moscato ; Margherita Venturini ; Stefania Affatato ; Mario Gaggiotti ; Nicola Bossini ; Francesco Scolari

Source :

RBID : PMC:7142691

Abstract

The outcome of SARS-CoV2 infection in patients who have received a kidney allograft and are being treated with immunosuppression is unclear. We describe 20 kidney transplant recipients (median age 59 years [inter quartile range 51-64 years], median age of transplant 13 years [9-20 years], baseline eGFR 36.5 [23-47.5]) with SARS-CoV2 induced pneumonia. At admission, all had immunosuppression withdrawn and were started on methylprednisolone 16 mg/day, all but one was commenced on antiviral therapy and hydroxychloroquine with doses adjusted for kidney function. At baseline, all patients presented fever but only one complained of difficulty in breathing. Half of patients showed chest radiographic evidence of bilateral infiltrates while the other half showed unilateral changes or no infiltrates. During a median follow-up of seven days, 87% experienced a radiological progression and among those 73% required escalation of oxygen therapy. Six patients developed acute kidney injury with one requiring hemodialysis. Six of 12 patients were treated with tocilizumab, a humanized monoclonal antibody to the IL-6 receptor. Overall, five kidney transplant recipients died after a median period of 15 days [15-19] from symptom onset. These preliminary findings describe a rapid clinical deterioration associated with chest radiographic deterioration and escalating oxygen requirement in renal transplant recipients with SARS-Cov2 pneumonia. Thus, in this limited cohort of long-term kidney transplant patients, SARS-CoV-2 induced pneumonia is characterized by high risk of progression and significant mortality.


Url:
DOI: 10.1016/j.kint.2020.04.002
PubMed: NONE
PubMed Central: 7142691

Links to Exploration step

PMC:7142691

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<p>The outcome of SARS-CoV2 infection in patients who have received a kidney allograft and are being treated with immunosuppression is unclear. We describe 20 kidney transplant recipients (median age 59 years [inter quartile range 51-64 years], median age of transplant 13 years [9-20 years], baseline eGFR 36.5 [23-47.5]) with SARS-CoV2 induced pneumonia. At admission, all had immunosuppression withdrawn and were started on methylprednisolone 16 mg/day, all but one was commenced on antiviral therapy and hydroxychloroquine with doses adjusted for kidney function. At baseline, all patients presented fever but only one complained of difficulty in breathing. Half of patients showed chest radiographic evidence of bilateral infiltrates while the other half showed unilateral changes or no infiltrates. During a median follow-up of seven days, 87% experienced a radiological progression and among those 73% required escalation of oxygen therapy. Six patients developed acute kidney injury with one requiring hemodialysis. Six of 12 patients were treated with tocilizumab, a humanized monoclonal antibody to the IL-6 receptor. Overall, five kidney transplant recipients died after a median period of 15 days [15-19] from symptom onset. These preliminary findings describe a rapid clinical deterioration associated with chest radiographic deterioration and escalating oxygen requirement in renal transplant recipients with SARS-Cov2 pneumonia. Thus, in this limited cohort of long-term kidney transplant patients, SARS-CoV-2 induced pneumonia is characterized by high risk of progression and significant mortality.</p>
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<contrib contrib-type="author" id="au1">
<name>
<surname>Alberici</surname>
<given-names>Federico</given-names>
</name>
<email>federico.alberici@unibs.it</email>
<xref rid="aff1" ref-type="aff">1</xref>
<xref rid="aff2" ref-type="aff">2</xref>
<xref rid="cor1" ref-type="corresp"></xref>
<xref rid="fn1" ref-type="fn"></xref>
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<contrib contrib-type="author" id="au2">
<name>
<surname>Delbarba</surname>
<given-names>Elisa</given-names>
</name>
<xref rid="aff2" ref-type="aff">2</xref>
<xref rid="fn1" ref-type="fn"></xref>
</contrib>
<contrib contrib-type="author" id="au3">
<name>
<surname>Manenti</surname>
<given-names>Chiara</given-names>
</name>
<xref rid="aff2" ref-type="aff">2</xref>
</contrib>
<contrib contrib-type="author" id="au4">
<name>
<surname>Econimo</surname>
<given-names>Laura</given-names>
</name>
<xref rid="aff2" ref-type="aff">2</xref>
</contrib>
<contrib contrib-type="author" id="au5">
<name>
<surname>Valerio</surname>
<given-names>Francesca</given-names>
</name>
<xref rid="aff2" ref-type="aff">2</xref>
</contrib>
<contrib contrib-type="author" id="au6">
<name>
<surname>Pola</surname>
<given-names>Alessandra</given-names>
</name>
<xref rid="aff2" ref-type="aff">2</xref>
</contrib>
<contrib contrib-type="author" id="au7">
<name>
<surname>Maffei</surname>
<given-names>Camilla</given-names>
</name>
<xref rid="aff2" ref-type="aff">2</xref>
</contrib>
<contrib contrib-type="author" id="au8">
<name>
<surname>Possenti</surname>
<given-names>Stefano</given-names>
</name>
<xref rid="aff2" ref-type="aff">2</xref>
</contrib>
<contrib contrib-type="author" id="au9">
<name>
<surname>Zambetti</surname>
<given-names>Nicole</given-names>
</name>
<xref rid="aff2" ref-type="aff">2</xref>
</contrib>
<contrib contrib-type="author" id="au10">
<name>
<surname>Moscato</surname>
<given-names>Marianna</given-names>
</name>
<xref rid="aff2" ref-type="aff">2</xref>
</contrib>
<contrib contrib-type="author" id="au11">
<name>
<surname>Venturini</surname>
<given-names>Margherita</given-names>
</name>
<xref rid="aff2" ref-type="aff">2</xref>
</contrib>
<contrib contrib-type="author" id="au12">
<name>
<surname>Affatato</surname>
<given-names>Stefania</given-names>
</name>
<xref rid="aff2" ref-type="aff">2</xref>
</contrib>
<contrib contrib-type="author" id="au13">
<name>
<surname>Gaggiotti</surname>
<given-names>Mario</given-names>
</name>
<xref rid="aff2" ref-type="aff">2</xref>
</contrib>
<contrib contrib-type="author" id="au14">
<name>
<surname>Bossini</surname>
<given-names>Nicola</given-names>
</name>
<xref rid="aff2" ref-type="aff">2</xref>
</contrib>
<contrib contrib-type="author" id="au15">
<name>
<surname>Scolari</surname>
<given-names>Francesco</given-names>
</name>
<xref rid="aff1" ref-type="aff">1</xref>
<xref rid="aff2" ref-type="aff">2</xref>
</contrib>
</contrib-group>
<aff id="aff1">
<label>1</label>
Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia Italy</aff>
<aff id="aff2">
<label>2</label>
Nephrology Unit, Spedali Civili Hospital, ASST Spedali Civili di Brescia, Brescia, Italy</aff>
<author-notes>
<corresp id="cor1">
<label></label>
Corresponding Author Federico Alberici. Associate Professor – Consultant in Renal Medicine, University of Brescia - ASST Spedali Civili, Piazzale Spedali Civili 1 25125 Brescia Tel +39 0303996880 Tel +39 0303995621 Tel +39 0303995626 Fax +39 0303996024
<email>federico.alberici@unibs.it</email>
</corresp>
<fn id="fn1">
<label></label>
<p id="ntpara0015">contributed equally to this work.</p>
</fn>
</author-notes>
<pub-date pub-type="pmc-release">
<day>9</day>
<month>4</month>
<year>2020</year>
</pub-date>
<pmc-comment> PMC Release delay is 0 months and 0 days and was based on .</pmc-comment>
<pub-date pub-type="epub">
<day>9</day>
<month>4</month>
<year>2020</year>
</pub-date>
<history>
<date date-type="received">
<day>28</day>
<month>3</month>
<year>2020</year>
</date>
<date date-type="rev-recd">
<day>3</day>
<month>4</month>
<year>2020</year>
</date>
<date date-type="accepted">
<day>3</day>
<month>4</month>
<year>2020</year>
</date>
</history>
<permissions>
<copyright-statement>© 2020 Published by Elsevier, Inc., on behalf of the International Society of Nephrology.</copyright-statement>
<copyright-year>2020</copyright-year>
<copyright-holder></copyright-holder>
<license>
<license-p>Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.</license-p>
</license>
</permissions>
<related-article related-article-type="article-reference" id="d32e271" ext-link-type="doi" xlink:href="10.1016/j.kint.2020.03.018"></related-article>
<related-article related-article-type="article-reference" id="d32e274" ext-link-type="doi" xlink:href="10.1016/j.kint.2020.04.001"></related-article>
<abstract id="abs0010">
<p>The outcome of SARS-CoV2 infection in patients who have received a kidney allograft and are being treated with immunosuppression is unclear. We describe 20 kidney transplant recipients (median age 59 years [inter quartile range 51-64 years], median age of transplant 13 years [9-20 years], baseline eGFR 36.5 [23-47.5]) with SARS-CoV2 induced pneumonia. At admission, all had immunosuppression withdrawn and were started on methylprednisolone 16 mg/day, all but one was commenced on antiviral therapy and hydroxychloroquine with doses adjusted for kidney function. At baseline, all patients presented fever but only one complained of difficulty in breathing. Half of patients showed chest radiographic evidence of bilateral infiltrates while the other half showed unilateral changes or no infiltrates. During a median follow-up of seven days, 87% experienced a radiological progression and among those 73% required escalation of oxygen therapy. Six patients developed acute kidney injury with one requiring hemodialysis. Six of 12 patients were treated with tocilizumab, a humanized monoclonal antibody to the IL-6 receptor. Overall, five kidney transplant recipients died after a median period of 15 days [15-19] from symptom onset. These preliminary findings describe a rapid clinical deterioration associated with chest radiographic deterioration and escalating oxygen requirement in renal transplant recipients with SARS-Cov2 pneumonia. Thus, in this limited cohort of long-term kidney transplant patients, SARS-CoV-2 induced pneumonia is characterized by high risk of progression and significant mortality.</p>
</abstract>
<abstract abstract-type="graphical" id="abs0015">
<title>Graphical abstract</title>
<fig id="undfig1" position="anchor">
<graphic xlink:href="fx1_lrg"></graphic>
</fig>
</abstract>
<kwd-group id="kwrds0010">
<title>Keywords</title>
<kwd>transplantation</kwd>
<kwd>acute kidney injury</kwd>
<kwd>inflammation</kwd>
<kwd>tocilizumab</kwd>
</kwd-group>
</article-meta>
</front>
<body>
<sec id="sec1">
<title>Introduction.</title>
<p id="p0010">SARS-CoV-2 infection is posing challenges to all the health systems in the world. The ideal therapeutic approach is still debated and data on subgroups of patients at high risk still scarce(1). We have developed an internal treatment protocol for the management of renal transplant patients with SARS-CoV-2 pneumonia (
<xref rid="bib2" ref-type="bibr">2</xref>
). Since the first days of March 2020 we re-organised our ward to admit kidney transplant patients with SARS-CoV2 pneumonia; we felt this rearrangement as necessary since our centre acts as referral for a population of 1200 kidney transplant patients. Due to the onset of the COVID-19 epidemic, acute transplantation surgery was suspended in our centre from the 20th of February 2020. The first admission of a transplant patient with SARS-CoV2 pneumonia occurred on the 27th of February 2020, the second one six days later and subsequently up to the 24thof March 2020 (day of when this analyses was performed and patients follow-up censored) an average rate of 1.2 kidney transplant patients were admitted per day . We describe here the clinical course and renal outcomes of the first 20 kidney transplant recipients admitted and followed in our unit with pneumonia secondary to SARS-CoV-2 infection.</p>
</sec>
<sec id="sec2">
<title>Results</title>
<p id="p0015">In this report we describe the progress of all kidney transplant patients with SARS-CoV2 pneumonia admitted up to the 24th of March 2020. These patients had a median inpatient stay of 7 days (IQR 4-15) and the main baseline clinical characteristics are shown in
<xref rid="tbl1" ref-type="table">Table 1</xref>
and
<xref rid="tbl2" ref-type="table">Table 2</xref>
. Briefly, all patients presented with fever, however only 1/20 complained of dyspnoea; 50% of the transplant patients had radiographic changes of bilateral infiltrates on admission, while the remaining 50% showed unilateral changes or no infiltrates; 7/20 did not require supplemental oxygen.
<table-wrap position="float" id="tbl1">
<label>Table 1</label>
<caption>
<p>Baseline clinical characteristics of 20 kidney transplant patients affected by SARS-CoV-2 infection followed in our unit</p>
</caption>
<table frame="hsides" rules="groups">
<thead>
<tr>
<th>Characteristics</th>
<th></th>
<th></th>
</tr>
</thead>
<tbody>
<tr>
<td>Male/Female</td>
<td></td>
<td>16/4</td>
</tr>
<tr>
<td>Age (years)</td>
<td></td>
<td>59 (IQR 51-64)</td>
</tr>
<tr>
<td>Comorbidities</td>
<td>Hypertension</td>
<td>85%</td>
</tr>
<tr>
<td></td>
<td>Ischemic cardiac disease</td>
<td>15%</td>
</tr>
<tr>
<td></td>
<td>Diabetes</td>
<td>15%</td>
</tr>
<tr>
<td></td>
<td>HCV infection</td>
<td>10%</td>
</tr>
<tr>
<td>Kidney transplant age (years)</td>
<td></td>
<td>13 (IQR 9-20)</td>
</tr>
<tr>
<td>Time from symptoms onset to admission (days)</td>
<td></td>
<td>5.5 (IQR 3.3-8)</td>
</tr>
<tr>
<td>Baseline serum Creatinine (mg/dl)</td>
<td></td>
<td>1.95 (IQR 1.5-2.8)</td>
</tr>
<tr>
<td>Baseline eGFR (ml/min)*</td>
<td></td>
<td>36.5 (IQR 23-47.5)</td>
</tr>
<tr>
<td>Baseline immunosuppression</td>
<td></td>
<td>CNIs 19/20
<break></break>
MMF 14/20
<break></break>
Low dose glucocorticoidˆ 13/20 mTORi 2/20</td>
</tr>
<tr>
<td>SARS-CoV-2 infection symptoms onset</td>
<td>Temperature (>37.5 °C)</td>
<td>100%</td>
</tr>
<tr>
<td></td>
<td>Cough</td>
<td>50%</td>
</tr>
<tr>
<td></td>
<td>Gastrointestinal symptoms</td>
<td>15%</td>
</tr>
<tr>
<td></td>
<td>Pharyngitis</td>
<td>10%</td>
</tr>
<tr>
<td></td>
<td>Shortness of breath</td>
<td>5%</td>
</tr>
<tr>
<td></td>
<td>Myalgia</td>
<td>5%</td>
</tr>
<tr>
<td>Chest X ray at hospital admission</td>
<td>No infiltrates</td>
<td>15%</td>
</tr>
<tr>
<td></td>
<td>Unilateral infiltrates</td>
<td>35%</td>
</tr>
<tr>
<td></td>
<td>Bilateral infiltrates</td>
<td>50%</td>
</tr>
<tr>
<td>Blood tests at hospital admission</td>
<td>WBC (NV 4,00 – 10,80 x10ˆ3/uL)</td>
<td>5470 (IQR 4115-6193)</td>
</tr>
<tr>
<td></td>
<td>Neutrophils (NV 1,50 – 8,00 x10ˆ3/uL)</td>
<td>3700 (IQR 2280-4500)</td>
</tr>
<tr>
<td></td>
<td>Lymphocytes (NV 0,90 – 4,00 x10ˆ3/uL)</td>
<td>1170 (IQR 620-1305)</td>
</tr>
<tr>
<td></td>
<td>Platelets (NV 130 – 400 x10ˆ3/uL)</td>
<td>196000 (IQR 119000-202000)</td>
</tr>
<tr>
<td></td>
<td>LDH (NV 135 – 225 U/L)</td>
<td>231 (IQR 190-260)</td>
</tr>
<tr>
<td></td>
<td>CPK (NV 39 – 308 U/L)</td>
<td>69 (IQR 44-121)</td>
</tr>
<tr>
<td></td>
<td>AST (NV 18 – 54 U/L)</td>
<td>37 (IQR 26-35)</td>
</tr>
<tr>
<td></td>
<td>ALT (NV 10 – 50 U/L)</td>
<td>23 (IQR 16-30)</td>
</tr>
<tr>
<td></td>
<td>Bilirubin (NV < 1,20 mg/dl)</td>
<td>0.8 (IQR 0.4-0.9)</td>
</tr>
<tr>
<td></td>
<td>CRP (NV < 5,0 mg/L)</td>
<td>49 (IQR 19-62)</td>
</tr>
<tr>
<td></td>
<td>Procalcitonine (NV < 0,5 ng/mL)</td>
<td>0.22 (IQR 0.1-0.35)</td>
</tr>
<tr>
<td></td>
<td>Ferritin (NV 30 – 400 ug/L)</td>
<td>831 (IQR 284-882)</td>
</tr>
<tr>
<td></td>
<td>Fibrinogen (NV 170 – 410 mg/d)</td>
<td>461 (IQR 343-614)</td>
</tr>
<tr>
<td></td>
<td>D-Dimer (NV < 232 ng/mL)</td>
<td>279 (IQR 277-563)</td>
</tr>
<tr>
<td></td>
<td>Urea (NV 17 – 49 mg/dL)</td>
<td>46 (IQR 48-106)</td>
</tr>
<tr>
<td></td>
<td>Creatinine (NV 0,70 – 1,20 mg/dL)</td>
<td>1.8 (IQR 1.7-3.5)</td>
</tr>
<tr>
<td>Antiviral therapy</td>
<td>Lopinavir/ritonavir</td>
<td>15/19</td>
</tr>
<tr>
<td></td>
<td>Darunavir + ritonavir</td>
<td>4/19</td>
</tr>
<tr>
<td>Ventilation requirement at hospital admission</td>
<td>No oxygen</td>
<td>7/20</td>
</tr>
<tr>
<td></td>
<td>LOR</td>
<td>8/20</td>
</tr>
<tr>
<td></td>
<td>HOR</td>
<td>5/20</td>
</tr>
<tr>
<td></td>
<td>NIV</td>
<td>0</td>
</tr>
<tr>
<td></td>
<td>MV</td>
<td>0</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<fn id="tspara0015">
<p>Data are reported as n(%) for categorical variables and median (interquartile range) for continuous variables.</p>
</fn>
<fn id="tspara0020">
<p>CNI: calcineurin inhibitors; MMF: mofetil mycophenolate; mTORi: mTOR inhibitors; LOR: low oxygen requirement; HOR: high oxygen requirement; NIV: non invasive ventilation; MV: mechanical ventilation; NV: normal value</p>
</fn>
<fn id="tspara0025">
<p>*Determined with the CKD-EPI equation</p>
</fn>
<fn id="tspara0030">
<p>ˆ Prednisone 5 mg/day or methylprednisolone 4 mg/day</p>
</fn>
</table-wrap-foot>
</table-wrap>
<table-wrap position="float" id="tbl2">
<label>Table 2</label>
<caption>
<p>Clinical characteristics and outcome of twenty kidney transplant patients with COVID 19 infection</p>
</caption>
<table frame="hsides" rules="groups">
<thead>
<tr>
<th></th>
<th>Age/Sex</th>
<th>Tx date</th>
<th>Co-morbidities</th>
<th>Respiratory and renal involvement</th>
<th>Baseline creatinine μmol/L (eGFR ml/min/1.73m
<sup>2</sup>
)</th>
<th>Baseline immunosuppression and treatment (+/- tocilizumab)</th>
<th>ACEi or ARB</th>
<th>Outcome</th>
</tr>
</thead>
<tbody>
<tr>
<td>1</td>
<td>70/F</td>
<td>12/2002</td>
<td>Hypertension</td>
<td>NIV</td>
<td>185 (23)</td>
<td>CNI/mTORi
<break></break>
COVID treatment: lopinavir/ritonavir + hydroxychloroquine
<break></break>
Dexamethasone</td>
<td>ACEi</td>
<td>Discharged</td>
</tr>
<tr>
<td>2</td>
<td>47/F</td>
<td>3/2011</td>
<td>None</td>
<td>ICU, AKI, ARDS</td>
<td>282 (16)</td>
<td>MMF/CNI/Low dose steroids
<break></break>
COVID treatment: lopinavir/ritonavir + hydroxychloroquine
<break></break>
Dexamethasone
<break></break>
Tociliizumab</td>
<td>ACEi</td>
<td>Inpatient</td>
</tr>
<tr>
<td>3</td>
<td>71/M</td>
<td>1/2007</td>
<td>Ischemic cardiac disease</td>
<td>NIV, ARDS</td>
<td>159 (37)</td>
<td>MMF/CNI/Low dose steroids
<break></break>
COVID treatment: lopinavir/ritonavir + hydroxychloroquine
<break></break>
Dexamethasone</td>
<td>ARB</td>
<td>Death</td>
</tr>
<tr>
<td>4</td>
<td>57/M</td>
<td>8/2018</td>
<td>HCV infection</td>
<td>ICU, ARDS</td>
<td>141 (47)</td>
<td>MMF/CNI/Low dose steroids
<break></break>
COVID treatment: lopinavir/ritonavir + hydroxychloroquine
<break></break>
Dexamethasone
<break></break>
Tocilizumab</td>
<td>NO</td>
<td>Death</td>
</tr>
<tr>
<td>5</td>
<td>51/M</td>
<td>3/1997</td>
<td>Hypertension
<break></break>
HCV infection</td>
<td>NIV</td>
<td>221 (29)</td>
<td>MMF/CNI
<break></break>
COVID treatment: lopinavir/ritonavir + hydroxychloroquine
<break></break>
Dexamethasone
<break></break>
Tocilizumab</td>
<td>NO</td>
<td>Discharged</td>
</tr>
<tr>
<td>6</td>
<td>46/M</td>
<td>9/ 2017</td>
<td>Hypertension</td>
<td>NIV</td>
<td>132 (55 )</td>
<td>MMF/CNI
<break></break>
COVID treatment: lopinavir/ritonavir + hydroxychloroquine
<break></break>
Dexamethasone</td>
<td>NO</td>
<td>Discharged</td>
</tr>
<tr>
<td>7</td>
<td>59/M</td>
<td>2/2015</td>
<td>Hypertension</td>
<td>ICU, ARDS</td>
<td>256 (23)</td>
<td>MMF/CNI/Low dose steroids
<break></break>
COVID treatment: lopinavir/ritonavir + hydroxychloroquine
<break></break>
Dexamethasone</td>
<td>ACEi</td>
<td>Death</td>
</tr>
<tr>
<td>8</td>
<td>70/F</td>
<td>7/2004</td>
<td>Hypertension</td>
<td>ICU, AKI, ARDS</td>
<td>300 (13)</td>
<td>CNI/Low dose steroids
<break></break>
COVID treatment: lopinavir/ritonavir + hydroxychloroquine
<break></break>
Dexamethasone</td>
<td>ACEi</td>
<td>Death</td>
</tr>
<tr>
<td>9</td>
<td>60/M</td>
<td>10/2011</td>
<td>Hypertension</td>
<td>Room air</td>
<td>150 (43 )</td>
<td>MMF/CNI/Low dose steroids
<break></break>
COVID treatment: lopinavir/ritonavir + hydroxychloroquine</td>
<td>ACEi</td>
<td>Inpatient</td>
</tr>
<tr>
<td>10</td>
<td>73/M</td>
<td>9/ 2013</td>
<td>Hypertension
<break></break>
Diabetes</td>
<td>NIV, ARDS</td>
<td>132 (46 )</td>
<td>MMF/CNI /low dose steroids
<break></break>
COVID treatment: lopinavir/ritonavir + hydroxychloroquine</td>
<td>ACEi</td>
<td>Inpatient</td>
</tr>
<tr>
<td>11</td>
<td>59/M</td>
<td>3/2010</td>
<td>Hypertension
<break></break>
Ischemic Cardiac disease
<break></break>
Diabetes</td>
<td>NIV, AKI, ARDS</td>
<td>238 (25)</td>
<td>MMF/Low dose steroids
<break></break>
COVID treatment: lopinavir/ritonavir + hydroxyhcloroquine
<break></break>
Dexamethasone
<break></break>
Tocilizumab</td>
<td>ARB</td>
<td>Inpatient</td>
</tr>
<tr>
<td>12</td>
<td>63/M</td>
<td>8/2004</td>
<td>Hypertension</td>
<td>NIV, ARDS</td>
<td>203 (29 ml/min)</td>
<td>MMF/CNI
<break></break>
COVID treatment: lopinavir/ritonavir + hydroxychloroquine
<break></break>
Dexamethasone
<break></break>
Tocilizumab</td>
<td>NO</td>
<td>Death</td>
</tr>
<tr>
<td>13</td>
<td>49/M</td>
<td>6/2018</td>
<td>Hypertension</td>
<td>NIV, AKI, ARDS</td>
<td>185 (36)</td>
<td>MMF/CNI/Low dose steroids
<break></break>
COVID treatment: lopinavir/ritonavir + hydroxychloroquine
<break></break>
Dexamethasone
<break></break>
Tocilizumab</td>
<td>NO</td>
<td>Inpatient</td>
</tr>
<tr>
<td>14</td>
<td>60/F</td>
<td>6/2018</td>
<td>Hypertension</td>
<td>NIV, ARDS</td>
<td>106 (49 )</td>
<td>MMF/CNI/Low dose steroids
<break></break>
COVID treatment: lopinavir/ritonavir + hydroxychloroquine</td>
<td>NO</td>
<td>Inpatient</td>
</tr>
<tr>
<td>15</td>
<td>57/M</td>
<td>6/2009</td>
<td>Hypertension</td>
<td>Room air</td>
<td>106 (67)</td>
<td>MMF/CNI
<break></break>
COVID treatment: lopinavir/ritonavir + hydroxychloroquine</td>
<td>NO</td>
<td>Inpatient</td>
</tr>
<tr>
<td>16</td>
<td>54/M</td>
<td>10/ 2002</td>
<td>Hypertension</td>
<td>NIV, AKI, ARDS</td>
<td>344 (16)</td>
<td>CNI/Low dose steroids
<break></break>
COVID treatment: darunavir + ritonavir + hydroxychloroquine</td>
<td>ARB</td>
<td>Inpatient</td>
</tr>
<tr>
<td>17</td>
<td>60/M</td>
<td>4/ 2007</td>
<td>Hypertension
<break></break>
Ischemic cardiac disease</td>
<td>Room air</td>
<td>141 (46 )</td>
<td>CNI
<break></break>
COVID treatment: lopinavir/ritonavir + hydroxychloroquine</td>
<td>NO</td>
<td>Inpatient</td>
</tr>
<tr>
<td>18</td>
<td>50/M</td>
<td>11/ 2010</td>
<td>Hypertension</td>
<td>Room air</td>
<td>123 (58 )</td>
<td>MMF/CNI/Low dose steroids
<break></break>
COVID treatment: darunavir + ritonavir + hydroxychloroquine</td>
<td>NO</td>
<td>Inpatient</td>
</tr>
<tr>
<td>19</td>
<td>69/M</td>
<td>7/ 1998</td>
<td>Hypertension
<break></break>
Diabetes</td>
<td>AKI</td>
<td>309 (17)</td>
<td>CNI/Low dose steroids
<break></break>
COVID treatment: darunavir + ritonavir + hydroxychloroquine</td>
<td>NO</td>
<td>Inpatient</td>
</tr>
<tr>
<td>20</td>
<td>44/M</td>
<td>7/2006</td>
<td>Hypertension</td>
<td>Room air</td>
<td>114 (66)</td>
<td>CNI mTORi
<break></break>
COVID treatment: darunavir + ritonavir + hydroxychloroquine</td>
<td>NO</td>
<td>Inpatient</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<fn>
<p>Legend: Yr=year, M=male, F=female, Y=yes, N=No, Aza=azathioprine, MMF=mycophenolate mofetil, ITU=intensive therapy unit, NIV=non-invasive ventilation, CVVH-continuous veno-venous haemofiltration, AKI-Acute Kidney injury, ARDS-Acute Respiratory Distress Syndrome).</p>
</fn>
</table-wrap-foot>
</table-wrap>
</p>
<p id="p0020">All patients had their usual transplant immunosuppression withdrawn and were started on methylprednisolone 16 mg or equivalent dose of prednisone, 19/20 received antiviral therapy and hydroxychloroquine as per our protocol (
<xref rid="bib2" ref-type="bibr">2</xref>
). As anti-viral therapy is known to interfere with calcineurin inhibitor metabolism, in four patients tacrolimus levels were monitored after these therapeutic changes were instituted. The median trough values before anti-viral therapy were 7.05 ng/ml(IQR 5.5-8.6); one patient had the level re-checked after 3 days with no change compared to baseline, one patient had the level rechecked 4 and 5 days after admission (-17% and -18% compared to baseline), one six days after admission (-12% compared to baseline) and one 8 days after admission (-21% compared to baseline). The median times from symptom onset and admission to these therapeutic changes were respectively 5 days (IQR 3-8.25) for antiviral therapy and 0 days (IQR 0-0) for hydroxychloroquine . During the follow-up one patient had hydroxychloroquine withdrawn due to toxicity (nausea, vomiting) but no prolongation of the cardiac QTc interval compared to baseline or cardiac arrhythmias were observed. Antibiotics were administered to 11/20 kidney transplant recipients (55%): cephalosporins in 64%, beta-lactams in 36%, fluoroquinolones in 25%, carbapenems in 10% and glycopeptides in 5%. During hospitalization chest radiographs were repeated in 15/20 patients and radiological findings worsened in 13/15 (87%). The changes of the main blood tests compared to baseline are shown in Supplementary Figure S1. In the individuals with worsening radiological findings, 11/13 (85%) required an escalation of the oxygen supplemental therapy; comprising: one patient switched from regular breathing to low oxygen requirement (LOR), 3/15 from regular breathing to high oxygen requirement (HOR), 2/15 from HOR to non-invasive ventilation (NIV) and 2/15 from HOR to mechanical ventilation (MV).</p>
<p id="p0025">Additional anti-inflammatory therapy comprising dexamethasone and tocilizumab were given to 11/20 (55%) and 6/20 (30%) patients, (see supplementary material for protocol details); in these patients, 4/11 (36%) and 2/6 (33%) subsequently died.</p>
<p id="p0030">The characteristics of the patients treated with tocilizumab are shown in
<xref rid="tbl3" ref-type="table">Table 3</xref>
; among these patients, 3/6 (50%) experienced a reduction of the oxygen requirements and 2/6 (33%) showed amelioration of the radiological findings. Two out of the six patients who were treated with tocilizumab eventually died and one was discharged from hospital 9 days after the administration of tocilizumab.
<table-wrap position="float" id="tbl3">
<label>Table 3</label>
<caption>
<p>Characteristics of 6 kidney transplant patients with SARS-CoV2 pneumonia treated with tocilizumab and outcome after treatment</p>
</caption>
<table frame="hsides" rules="groups">
<thead>
<tr>
<th></th>
<th>Day of tocilizumab administration</th>
<th>Oxygen requirement at tocilizumab</th>
<th>Follow up post tocilizumab (days)</th>
<th>Oxygen requirement after tocilizumab</th>
<th>Chest X ray improvement</th>
<th>Outcome</th>
</tr>
</thead>
<tbody>
<tr>
<td>
<bold>Patient 1</bold>
</td>
<td>Day 6</td>
<td>NIV</td>
<td>11</td>
<td>HOR</td>
<td>No</td>
<td>Inpatient</td>
</tr>
<tr>
<td>
<bold>Patient 2</bold>
</td>
<td>Day 6</td>
<td>HOR</td>
<td>10</td>
<td>MV</td>
<td>No</td>
<td>Death</td>
</tr>
<tr>
<td>
<bold>Patient 3</bold>
</td>
<td>Day 7</td>
<td>LOR</td>
<td>9</td>
<td>Room air</td>
<td>No</td>
<td>Discharged</td>
</tr>
<tr>
<td>
<bold>Patient 4</bold>
</td>
<td>Day 3</td>
<td>HOR</td>
<td>4</td>
<td>HOR</td>
<td>Yes</td>
<td>Inpatient</td>
</tr>
<tr>
<td>
<bold>Patient 5</bold>
</td>
<td>Day 5</td>
<td>NIV</td>
<td>3</td>
<td>NIV</td>
<td>NA</td>
<td>Death</td>
</tr>
<tr>
<td>
<bold>Patient 6</bold>
</td>
<td>Day 4</td>
<td>HOR</td>
<td>3</td>
<td>LOR</td>
<td>Yes</td>
<td>Inpatient</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<fn>
<p>LOR: low flux oxygen; HOR: high flux oxygen; NIV: non invasive ventilation; MV: mechanical ventilation</p>
</fn>
</table-wrap-foot>
</table-wrap>
</p>
<p id="p0035">In terms of kidney function, the medium creatinine level at admission was +17% (IQR 12-26%, range 0 – 143%) compared to baseline and the highest creatinine level observed during the follow-up was +33% (IQR 13-59%, range 0 - 157%) compared to baseline; 6/20 patients developed AKI and 1/6 required haemodialysis.</p>
<p id="p0040">During follow-up, 4/20 (20%) patients required intensive care and three of these individuals subsequently died. Overall, 5/20 patients died after a median of 11 days from admission (IQR 11-14) and 15 days (IQR 15-19) from symptom onset; 4/5 patients died from complications of the respiratory failure secondary to SARS-Cov2 infection, 1/5 died of probable bacterial sepsis (fever, rise of CRP and procalcitonin) despite a satisfactory recovery from SARS-Cov2 pneumonia induced respiratory failure, need for ICU care and treatment with dexamethasone and tocilizumab.</p>
<p id="p0045">Three patients were discharged, after 7 days in one case and after 16 in the 2 remaining cases; at discharge creatinine level compared to baseline was 3.6 vs 2.1, 2.3 vs 2.5 and 2.1 vs 1.5 mg/dl. In terms of immunosuppressive therapy, two patients were discharged receiving methylprednisolone 16 mg and one with methylprednisolone 12 mg per day.</p>
</sec>
<sec id="sec3">
<title>Discussion</title>
<p id="p0050">SARS-CoV2 infection is challenging health care systems around the world. The mortality of the disease has been proposed to be around the 2.3% with age and comorbidities such as cardiovascular diseases, diabetes, chronic respiratory diseases, hypertension and cancer being associated with worse prognoses (
<xref rid="bib4" ref-type="bibr">4</xref>
,
<xref rid="bib5" ref-type="bibr">5</xref>
). Immunosuppression and CKD may represent additional risk factors, although specific data are not available at the moment. Here we reported the clinical characteristics and the outcomes of the first 20 kidney transplant patients affected by SARS-CoV2 pneumonia at our centre. Despite on average a relatively benign onset of the disease, a large proportion of the patients displayed worsening chest radiology and required an escalation of the supplemental oxygen. Of note, 25% of the patients died despite an aggressive approach to immunosuppression withdrawal and early commencement of antiviral therapy.</p>
<p id="p0055">The role of lopinavir/ritonavir in SARS-CoV2 management is debated, with some data supporting a greater benefit with early start compared to a delayed commencement (
<xref rid="bib1" ref-type="bibr">1</xref>
); our cohort was started on antiviral therapy a median of 5.5 days after symptom onset. Lopinavir/ritonavir may interact with CNIs impacting on their level: the four patients of our cohort with serial CNI monitoring confirmed that; of note none of these patients died and 3/4 have been discharged.</p>
<p id="p0060">Reports suggest a role for hydroxychloroquine treatment in reducing the viral load(6). In our cohort, 19/20 patients received this drug although toxicity led to treatment withdrawal in one case.</p>
<p id="p0065">Hydroxychloroquine and lopinavir/ritonavir may interact causing a prolongation of the cardiac QTc, interval however none of this series experienced this complication. Preliminary data and understanding of the pathogenesis of the pneumonia secondary to SARS-CoV-2 infection suggest a central role of inflammatory cytokines in inducing the rapid clinical deterioration in association with worsening chest radiology and escalating oxygen requirement , observed in an average of 7-10 days from the symptom onset(7). In this context glucocorticoids and tocilizumab have been suggested to be a therapeutic strategy(8). Our subgroup of patients treated by this approach experienced a poor outcome, although encouraging signals in terms of potential beneficial effects were observed in the patients treated with tocilizumab: 50% reduced oxygen therapy requirement and 33% experiencing improvement of radiological changes. Despite that, two patients died. Our results are too preliminary and the sample size too small to draw firm conclusions.</p>
<p id="p0070">The high mortality rate of this population suggests aggressive management is needed for kidney transplant patients with SARS-CoV2 infection, in particular early hospitalization should be considered in case of pneumonia; furthermore more effective treatment protocols need to be identified.</p>
<p id="p0075">Our study has limitations: the sample size is small and the median follow-up short; findings are, therefore, preliminary and will need to be confirmed in bigger cohorts with longer follow-up. Some strengths may be acknowledged as well and in particular the monocentric approach and the homogeneity of the clinical treatment employed.</p>
<p id="p0080">In conclusion, kidney transplant patients with SARS-CoV2 pneumonia may present with an unfavourable disease course and a poor outcome; hospitalization is required and repeat chest x-ray advisable. Clinical management needs to be improved in order to impact on these patients’ prognosis.</p>
</sec>
<sec id="sec4">
<title>Methods</title>
<p id="p0085">All the kidney transplant patients with SARS-CoV-2 infection admitted in the Nephrology Unit of the Spedali Civili Hospital of Brescia have been included. The therapeutic approach followed our protocol already published on the website of the European Renal Association (ERA-EDTA)(
<xref rid="bib2" ref-type="bibr">2</xref>
). In brief, all admitted patients had immunosupression withdrawn and were commenced on methylprednisolone 16 mg/daily. Antiviral therapy with Lopinavir/Ritonavir plus hydroxychloroquine (dose adjusted for kidney function) was considered in all patients if not contraindicated. In case of shortage of Lopinavir/Ritonavir, Darunavir and Ritonavir have been employed (
<italic>supplementary material</italic>
). Patients experiencing clinical deterioration after at least 7 days from symptom onset or no temperature for >72h but with escalating oxygen requirements or progression of the chest radiology and no signs of bacterial infection were considered for dexamethasone (20 mg/daily for 5 day, then 10 mg/daily for 5 days) and up to two tocilizumab infusions at intervals of 12-24 hours (8 mg/kg of body weight, maximum dose per infusion 800 mg). Details on the indications for dexamethasone and tocilizumab have been provided in the
<italic>supplementary materials</italic>
.</p>
<p id="p0090">Oxygen requirements have been categorised as follow: no oxygen needs, low oxygen requirement (LOR), from nasal cannula up to Venturi mask with FiO2 of 0.5), high oxygen requirement (HOR, including Venturi mask with FiO2 of 0.6, reservoir mask with oxygen at 15l/min and high-flow nasal ventilation), non-invasive ventilation (NIV) and mechanical ventilation (MV). Acute kidney injury (AKI) was defined as per previous publications(3).</p>
<p id="p0095">Considering the well documented effects of lopinavir/ritonavir and hydroxychloroquine on increasing the cardiac QTc interval , electrocardiograms were performed every 2-3 days; in case of prolongation compared to baseline, dose reduction was performed.</p>
<p id="p0100">Due to the small sample size, only descriptive statistics have been performed, results are expressed as n(%) for categorical variables and median and interquartile range (IQR) for continuous variables.</p>
<p id="p0105">According to the Italian regulations, ethical approval for the study has been obtained.</p>
</sec>
<sec id="sec5">
<title>Uncited reference</title>
<p id="p0110">
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,
<xref rid="bib6" ref-type="bibr">6.</xref>
,
<xref rid="bib7" ref-type="bibr">7.</xref>
,
<xref rid="bib8" ref-type="bibr">8.</xref>
.</p>
</sec>
</body>
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<sec id="appsec1" sec-type="supplementary-material">
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<p id="ntpara0010">Conflict of interest: the authors declare no conflict of interest.</p>
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</back>
</pmc>
</record>

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