key: cord-0991982-6njzj7mx authors: Meshram, Hari S.; Kute, Vivek B.; Patel, Himanshu; Banerjee, Subho; Navadiya, Vijay; Desai, Sudeep; Rizvi, Syed J; Mishra, Vineet; Chauhan, Sanshriti title: Feasibility and safety of remdesivir in SARS‐CoV2 infected renal transplant recipients: A retrospective cohort from a developing nation date: 2021-05-18 journal: Transpl Infect Dis DOI: 10.1111/tid.13629 sha: 71cf6020d97765f4a2b89f7d69f7c5eae781d0cf doc_id: 991982 cord_uid: 6njzj7mx INTRODUCTION: Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV2) infection has drastically impacted the transplant communities. Remdesivir (RDV) has shown some promising results in coronavirus disease (COVID‐19) albeit with low certainty. Data in kidney transplant recipients (KTR) are still lacking. METHODS: This was a retrospective cohort of 57 moderate to severe COVID‐19 positive KTR in a single center who received RDV as a part of COVID‐19 management. No dose adjustments were done. The outcomes were measured as acute kidney injury (AKI) recovery; liver function tests abnormalities; other side effects; graft loss and death. RESULTS: The median (inter‐quartile range) age of presentation was 44 (31‐51) years. The duration from onset of symptoms to RDV initiation was 6 (5‐7) days. Thirty‐two (56%) cases received RDV on the day of admission. Forty‐six (81%) cases were on oxygen support upon initiation of RDV. Thirty‐eight (66.6%) cases had acute kidney injury on admission. The median baseline, admission, and 28‐day follow‐up serum creatinine of the cohort were 1.59 (1.1‐2.1), 2.13 (1.3‐3.1), and 1.58 (1.05‐2.1) mg/dl, respectively. A total of 8(14%) cases died in the study with 1 (1.7%) graft loss. All those cases that died were on oxygen therapy at the time of initiation of RDV. No liver function derangements or any other major adverse events with the drug were reported. CONCLUSION: RDV therapy is safe and clinically feasible in renal transplant recipients as seen in our cohort. Larger clinical registries and randomized clinical trials should be conducted to further explore the efficacy in transplant recipients. SARS-CoV2 pandemic has medically, economically and psychosocially upended the world. Globally as of 11 April 2021, there have been 134,957,021 confirmed cases of COVID-19, including 2,918,752 deaths, reported to the WHO. 1 India ranks second in the number of COVID-19 cases worldwide as updated by the WHO. As per the Ministry of health and family welfare India (MOHF), COVID-19 has a 90.44% recovery rate and 1.27% mortality. 2 ing severe COVID-19 disease. 3 Since the outbreak, many therapies have been tested but only steroids have shown mortality benefit. Remdesivir (RDV) appears to hold promise as an anti-viral agent that could be effective against SARS-CoV2. RDV is an intravenous (IV) drug that acts by inhibiting viral RNA polymerase and has shown broad-spectrum activity against viruses like Ebola, severe acute respiratory syndrome virus (SARS) and in animal models of SARS-CoV2. [4] [5] [6] Few studies in the general population have also shown encouraging results. [7] [8] [9] [10] Recently, a few studies have shown that RDV can be used in hemodialysis, acute kidney injury and chronic kidney disease. [11] [12] [13] However, we still have limited data regarding the effectiveness of RDV in the setting of transplant recipients. Till date, this remains the largest cohort of KTR who have received RDV therapy. The study was designed as a retrospective observational study. The research methodology was done in accordance with strengthening the reporting of observational studies in epidemiology (STROBE) statement. Data were extracted from the Institute of Kidney Diseases and Research Centre, Dr H L Trivedi Institute of Transplantation Sciences, Ahmedabad, Gujarat, India, which is an organ transplantation center and functioned as a dedicated COVID-19 center to combat the COVID-19 surge in the country. A total of 57 KTR with moderate to severe SARS-CoV2 received RDV from 4 July 2020 to 14 November 2020. KTR who had a positive SARS-CoV2 polymerase chain reaction (PCR) from a nasopharyngeal or oropharyngeal swab and moderate to severe illness were eligible for the study. Moderate SARS-CoV2 was defined as radiological or clinical evidence of pneumonia and oxygen saturation ≥94%; while severe had saturation below <94% or lung infiltrates >50% or respiratory rate >30 breaths/minute. 14 KTR were managed as per the availability of resources and the national guidelines. 15 RDV was used in all severe cases and moderate cases having a high risk of progression based on clinical and laboratory profile. RDV was administered in a dose of 200 mg OD on the first day, followed by 100 mg OD for the subsequent 10 days. RDV was stopped early on a case-to-case basis as per the treating clinician's discretion. Exclusion criteria included an elevation of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) >5 times the upper limit of normal range (ULN) or a history of liver disease. Low estimated glomerular filtration rate (eGFR) and AKI were not considered as an exclusion criterion in the study. Intravenous methylprednisolone at a dosage of 1mg/kg was used in all cases requiring oxygen therapy; subcutaneous unfractionated heparin 5000 IU or low molecular weight heparin was used in all cases with raised inflammatory markers. Immunosuppression was curtailed by cessation of antimetabolite in all moderate and severe cases. Calcineurin inhibitors (CNI) were reduced or stopped on a case-to-case basis. Other investigational therapies like tocilizumab and COVID-19 convalescent plasma therapy were advised as per the local availability and severity of COVID-19. Demographic and clinical characteristics of KTR were recorded which included age, sex, comorbidities, duration of symptoms, blood group and transplant date. Clinical status was recorded daily which comprised of the heart rate, respiratory rate, blood pressure, temperature, oxygen saturation and the daily modified WHO ordinal scale. 16 The 7-point ordinal scale was as follows: (7) Death; (6) KTR on invasive mechanical ventilation; (5) KTR on noninvasive ventilation or high flow oxygen devices; (4) KTR on supplemental oxygen; (3) Hospitalized KTR but on room air; (2) Not hospitalized, limitation on activities; (1) Not hospitalized, no limitations on activities. Serial routine laboratory parameters were planned every third day and repeat RT-PCR was sent depending on the clinical status. Time to viral resolution cannot be interpreted as the timing of repeat RTPCR was not uniform in all of the cases. Other than the routine blood chemistries inflammatory markers including Lactate dehydrogenase (LDH), Interleukin 6 (IL-6), Ferritin, D-dimer levels and high-sensitivity Creactive protein (hs-CRP) were followed for serial trends. The cutoff for the measurement of inflammatory markers implying severity was obtained from previously published larger studies. 17, 18 All the blood reports were electronically retrieved from the online hospital database. Baseline eGFR on admission was calculated as per the CKD-EPI 2009. The outcomes were measured in terms of AKI recovery at discharge or on 28-day follow-up; graft loss; aspartate transaminase (AST), alanine transaminase (ALT) levels >5times the ULN and any other adverse events. AKI was defined as an increase in serum creatinine by 0.3 mg/dl or more within 48 hours or an increase to 1.5 times or more from baseline based on the Kidney Disease: Improving Global Outcomes (KDIGO) definition. Complete AKI recovery was defined as serum creatinine reaching the baseline status at 28-day followup and partial recovery was defined as serum creatinine declining but remaining above the baseline values. No recovery was defined as graft loss that caused initiation of renal replacement therapy. Outcome was also measured in terms of improvement in the modified WHO ordinal scale. Improvement was defined as a reduction of a 2-point or 1-point in the scale from baseline levels to 28-day or discharge from the hospital. This was an open-label study of an investigational drug and hence no predefined sample size was calculated. Variables were expressed in number, percentage, median, inter-quartile range (IQR) as appropriate. All analysis was done by SPSS software version 1. A total of 92 post-transplant COVID-19 cases were admitted from 4 July 2020 to 14 November 2020 in the institute of which 57 moderate to severe COVID-19 cases received RDV therapy. Table 1 shows the demographic characteristics of the recipients. The median (inter-quartile range) age of presentation was 44 years. The most common age group affected was 18-50 years (39, 68%). Forty-seven (82%) cases were males in the cohort. The blood group distribution of the cohort was A (10, 18%), B (22, 38 Table S1 shows the detailed laboratory profile of the cohort. The median (IQR) hemoglobin of the cohort was 11.5 (9.9-13.3) g/dl, cases who succumbed to their illness. The world still hopes and fights for the definitive therapy of SARS-CoV2. After dismal performances by various promising therapies, 19, 20 RDV emerged with some hope in May 2020. RDV is an adenosine The pharmacokinetics, pharmacodynamics and safety profile of RDV is less well studied in the transplant settings. Due to concomitant immunosuppression and chances of drug-drug interaction the potential issue of tolerability and efficacy also remain incompletely Animal studies have shown concern about the liver and renal injuries with SBECD accumulation. 33 The ministry of health and family This was a retrospectively designed study, and the control group for outcome measurement was not possible. Only two of the KTR in the cohort were over 65 years, and advanced age is considered a major risk factor for mortality in COVID-19. Also, other investigational therapies like plasma and tocilizumab were given which also could confound results. It is also noteworthy that no patient was on a ventilator or extracorporeal membrane oxygenation at the start of the therapy, so our findings cannot be applied to these groups of patients. Viral load measurement would have further supported the improvement in clinical status observed in our study. Even though the sample size was small, still an overall 84% survival rate achieved in RDV receiving moderate to severe SARS-CoV2 post-transplants is a good outcome compared to previous reports where mortality in moderate to severe cases was reported high. 24, 25 Accordingly, larger clinical registries and randomized clinical trials involving patients from the immunosuppressed group will further provide evidence for the drug. RDV was a feasible and safe therapeutic option in our cohort which All authors have made substantial contribution in research design, performance of the research, data collection, data analysis, writing and approval of final version the paper. Data is available from the corresponding author on reasonable request. 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