ABSTRACT Introduction COVID-19 is associated with endothelial activation and systemic inflammation; consequently, statins can be used in its treatment as they have anti-inflammatory, antithrombotic, and profibrinolytic properties and may interfere with COVID-19 viral entry into cells through disruption of cell membrane lipid rafts. Objective We performed a meta-analysis of randomized clinical trials that compared statin therapy to placebo or to standard care in adult patients hospitalized for COVID-19. Methods We searched the MEDLINE, EMBASE, and Cochrane Library databases for all-cause mortality, hospitalization duration, and admission to the intensive care unit. Results Of the 228 studies reviewed, four studies were included, with a total of 1,231 patients, of whom 610 (49.5%) were treated with statins. There was no significant difference in all-cause mortality (odds ratio [OR] 0.96; 95% confidence interval [95%CI]: 0.61-1.51; p=0.86; I2=13%), duration of hospitalization (mean difference [MD] 0.21; 95%CI: -1.74-2.16; p=0.83; I2=92%), intensive care unit admission (OR= 3.31; 95%CI: 0.13-87.1; p=0.47; I2=84%), need for mechanical ventilation (OR= 1.03; 95%CI: 0.36-2.94; p=0.95; I2=0%), or increase in liver enzyme levels (OR= 0.58; 95%CI: 0.27-1.25; p=0.16; I2=0%) between patients treated with or without statin therapy. Conclusion Our findings suggest that in adult patients hospitalized with COVID-19, statin therapy results in no difference in clinical outcomes when compared to outcomes by placebo or standard of care. Prospero database registration: (www.crd.york.ac.uk/prospero) under the number CRD42022338283. COVID19 COVID 19 COVID-1 inflammation consequently antiinflammatory, antiinflammatory anti inflammatory, inflammatory anti-inflammatory antithrombotic rafts metaanalysis meta analysis COVID19. 19. MEDLINE EMBASE allcause all cause 22 reviewed included 1231 1 231 1,23 61 49.5% 495 49 5 (49.5% odds OR [OR 0.96 096 0 96 95 95%CI 95CI CI [95%CI] 0.611.51 061151 0.61 1.51 51 0.61-1.51 p=0.86 p086 p 86 I2=13%, I213 I I2=13% , I2 13 I2=13%) mean MD [MD 0.21 021 21 1.742.16 174216 1.74 2.16 74 2 16 -1.74-2.16 p=0.83 p083 83 I2=92%, I292 I2=92% 92 I2=92%) OR= (OR 3.31 331 3 31 0.1387.1 013871 0.13 87.1 87 0.13-87.1 p=0.47 p047 47 I2=84%, I284 I2=84% 84 I2=84%) 1.03 103 03 0.362.94 036294 0.36 2.94 36 94 0.36-2.94 p=0.95 p095 I2=0%, I20 I2=0% 0.58 058 58 0.271.25 027125 0.27 1.25 27 25 0.27-1.25 p=0.16 p016 COVID19, 19, registration www.crd.york.ac.uk/prospero wwwcrdyorkacukprospero www crd york ac uk prospero (www.crd.york.ac.uk/prospero CRD42022338283 CRD COVID1 COVID- 123 23 1,2 6 49.5 4 (49.5 0.9 09 9 [95%CI 611 0.611.5 06115 061 0.6 151 1.5 0.61-1.5 p=0.8 p08 8 I21 I2=13 0.2 02 742 1.742.1 17421 174 1.7 216 2.1 7 -1.74-2.1 I29 I2=92 3.3 33 1387 0.1387. 01387 013 0.1 871 87. 0.13-87. p=0.4 p04 I28 I2=84 1.0 10 362 0.362.9 03629 036 0.3 294 2.9 0.36-2.9 p=0.9 p09 I2=0 0.5 05 271 0.271.2 02712 027 125 1.2 0.27-1.2 p=0.1 p01 CRD4202233828 12 1, 49. (49. 0. 0.611. 0611 06 15 1. 0.61-1. p=0. p0 I2=1 1.742. 1742 17 2. -1.74-2. I2=9 3. 138 0.1387 0138 01 0.13-87 I2=8 0.362. 0362 29 0.36-2. I2= 0.271. 0271 0.27-1. CRD420223382 (49 0.611 0.61-1 p=0 1.742 -1.74-2 0.138 0.13-8 0.362 0.36-2 0.271 0.27-1 CRD42022338 (4 0.61- p= -1.74- 0.13- 0.36- 0.27- CRD4202233 ( -1.74 CRD420223 -1.7 CRD42022 -1. CRD4202 -1 CRD420 - CRD42 CRD4

Resumo COVID-19 é uma pandemia associada a manifestações clínicas sistêmicas. Neste estudo, apresenta-se revisão narrativa acerca do envolvimento renal na COVID-19. Envolvimento renal parece ser relacionado a efeitos citopáticos diretos, mecanismos imunológicos, efeitos indiretos de outros mediadores no tecido renal, além de disfunção e lesão de outros órgãos. A evolução da COVID-19 pode ser complicada por lesão renal aguda (LRA) em percentual significativo dos pacientes, e a disfunção renal parece ser associada a pior prognóstico. Pacientes com doença renal crônica (DRC) parecem ser mais suscetíveis a formas severas da COVID-19. Pacientes em terapia de substituição renal (TSR) contínua também constituem população vulnerável em razão de idade avançada, comorbidades subjacentes, resposta imune disfuncional e aglomeração em unidades de diálise, com necessidade de visitas frequentes aos serviços de saúde. Pacientes transplantados renais podem estar em alto risco dadas imunossupressão a longo prazo e comorbidades; assim, o manejo da imunossupressão é mandatório. Finalmente, TSR pode ser necessária durante a COVID-19, e diferentes modalidades são discutidas conforme manifestações clínicas e aspectos laboratoriais. Assim, COVID-19 parece acometer os rins por diferentes mecanismos, os quais contribuem para o desenvolvimento de LRA e aumento da severidade da doença. Ainda, pacientes com DRC e transplantados renais apresentam elevado risco para desenvolvimento de COVID-19 e de mortalidade.

Abstract COVID-19 is a pandemic associated with systemic clinical manifestations. In this study, we aimed to present a narrative review on kidney involvement in COVID-19. Kidney involvement could be derived from direct cytopathic effects, immunological mechanisms, indirect effects on renal tissue through other mediators, and dysfunction or injury of other organs. The evolution of COVID-19 may be complicated with acute kidney injury (AKI) in a significant percentage of patients, and renal dysfunction seems to be associated with worse prognosis. Patients with chronic kidney disease (CKD) seem to be more susceptible to the severe forms of COVID-19. Patients with renal replacement therapy (RRT) are also a vulnerable population as consequence of their advanced age, underlying comorbidities, impaired immune response, and clustering in hemodialysis centers, with requirements for frequent contact with healthcare services. Kidney transplant patients may be at high-risk due to long-term immunosuppression and comorbidities, hence, managing immunosuppression is imperative. Lastly, renal replacement therapy may be required during COVID-19, and different modalities are discussed based on clinical findings and laboratorial aspects. Therefore, COVID-19 seems to affect kidney by different mechanisms, which contributes for AKI development and increases the severity of the disease. Also, patients with CKD and kidney transplant recipients are at higher risk for COVID-19 and mortality.