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      Cyclosporine as preferred calcineurin inhibitor in renal allograft recipients with COVID-19 infection

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          Abstract

          To the Editor Kidney International recently published two series of renal allograft recipients with COVID-19 infection including different approaches to maintenance immunosuppression. While Alberici et al. 1 report withdrawal of baseline immunosuppression in 20 patients with COVID-19 pneumonia and mainly continuation with methylprednisolone, Banerjee et al. 2 pursued more gentle reduction of immunosuppression with mainly discontinuation of the antimetabolite in 7 patients with COVID-19 infection of varying severity. However, in 2 of the 7 patients the calcineurin inhibitor Tacrolimus was additionally stopped because of severe respiratory distress syndrome. The corresponding editorial 3 suggests switching to the calcineurin inhibitor cyclosporine as a possible further approach for future exploration as in vitro data report suppression of viral replication for various coronaviruses at noncytotoxic concentrations regardless of immunosuppressive effects of cyclosporine. 4 In line with this, we report the first renal allograft recipient converted to cyclosporine during COVID-19 infection. The 45-year-old male had been transplanted 16 years ago. His immunosuppression consisted of only the antimetabolite mycophenolate mofetil. On admission the patient presented with typical symptoms of COVID-19 pneumonia including fever, cough, dyspnea and crazy paving pattern in CT scan. Main characteristics are summarized in Table 1 . The therapeutic regimen consisted of withdrawal of the antimetabolite, conversion to low-dose steroid and introduction of low-dose cyclosporine, azithromycin and hydroxychloroquine. He required mechanical ventilation for four days until his general condition improved significantly and the patient could be discharged after 17 days with stable allograft function. Therefore, switching to a Cyclosporine-based immunosuppression may represent another therapeutic option in the case of COVID-19 infection following kidney transplantation. Table 1 (according to 2 ): Clinical characteristics, outcome and blood parameters of first kidney transplant patient converted to cyclosporine during COVID-19 infection Patient Age/sex Tx date Comorbidities Respiratory and renal involvement Baseline creatinine (eGFR ml/min per 1.73 m2) Baseline immunosuppression and treatment ACEI or ARB Outcome 1 45/M 2004 HT/ hypercholisterin-aemia Yes, ARDS + AKI (without need for RRT) 124-141 (51-59) MMFMMF stopped and switch to CyA/Pred No Discharged from ITU,now at home,full recovery Cont. with Patient White cell count (x 10 9 /l) (3.9-9.8) Lymphocyte count (x 10 9 /l) (1.1-3.2) Serum CRP (mg/l) (<5) Serum ferritin (μg/l) (30-400) Serum D dimer (μg/l) (0-500) Serum LDH (U/l) (<249) Serum troponin T (ng/l) (<14) 1 7.4 (D1) 1.18 (D4) 18 (D1),289 (D8) 2563 (D9) 600 (D2),8800 (D10) 346 (D2),634 (D9) <13 ACEI, angiotensin-converting enzyme inhibitor; AKI, acute kidney injury; ARB, angiotensin receptor blocker; ARDS, acute respiratory distress syndrome; Cont., continued; COVID-19, coronavirus disease 2019; CRP, C-reactive protein; CyA, cyclosporine A; D, day after admission; D1, day of admission; eGFR, estimated glomerular filtration rate; HT, hypertension; LDH, lactate dehydrogenase; ITU, intensive therapy unit; M, male; MMF, mycophenolate mofetil; Pred, prednisolone; RRT, renal replacement therapy; Tx, treatment

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          Cyclosporin A inhibits the replication of diverse coronaviruses.

          Low micromolar, non-cytotoxic concentrations of cyclosporin A (CsA) strongly affected the replication of severe acute respiratory syndrome coronavirus (SARS-CoV), human coronavirus 229E and mouse hepatitis virus in cell culture, as was evident from the strong inhibition of GFP reporter gene expression and a reduction of up to 4 logs in progeny titres. Upon high-multiplicity infection, CsA treatment rendered SARS-CoV RNA and protein synthesis almost undetectable, suggesting an early block in replication. siRNA-mediated knockdown of the expression of the prominent CsA targets cyclophilin A and B did not affect SARS-CoV replication, suggesting either that these specific cyclophilin family members are dispensable or that the reduced expression levels suffice to support replication.
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            Author and article information

            Contributors
            Journal
            Kidney Int
            Kidney Int
            Kidney International
            Published by Elsevier, Inc., on behalf of the International Society of Nephrology.
            0085-2538
            1523-1755
            4 June 2020
            4 June 2020
            Affiliations
            [1 ]Transplant Center, University Hospital Munich, Ludwig-Maximilians-University (LMU), Munich, Germany
            [2 ]Department of General, Visceral, and Transplant Surgery, University Hospital Munich, Ludwig-Maximilians-University (LMU), Munich, Germany
            [3 ]Nephrology Division, Medizinische Klinik und Poliklinik IV, University Hospital Munich, Ludwig-Maximilians-University (LMU), Munich, Germany
            Author notes
            []Correspondence: Dr. Stephan Kemmner Transplantationszentrum München, Klinikumder Universität München, Marchioninistraße 15, 81377 München, Germany stephan.kemmner@ 123456med.uni-muenchen.de
            Article
            S0085-2538(20)30628-1
            10.1016/j.kint.2020.05.024
            7270808
            © 2020 Published by Elsevier, Inc., on behalf of the International Society of Nephrology.

            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.

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            Nephrology

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