key: cord-0731624-5guxx9ph authors: León-Román, Juan; Agraz, Irene; Vergara, Ander; Ramos, Natalia; Toapanta, Nestor; García-Carro, Clara; Gabaldón, Alejandra; Bury, Roxana; Bermejo, Sheila; Bestard, Oriol; Soler, María José title: COVID-19 infection and renal injury: where is the place for acute interstitial nephritis disease? date: 2022-03-14 journal: Clin Kidney J DOI: 10.1093/ckj/sfac079 sha: 5673d8410d3107036c2c93905a5dece2ffc78874 doc_id: 731624 cord_uid: 5guxx9ph Novel coronavirus disease infection (COVID-19) was declared a global pandemic in March 2020 and since then has become a major public health problem. The prevalence of COVID-19 infection and acute kidney injury (AKI) is variable depending on several factors such as race/ethnicity, and severity of illness. The pathophysiology of renal involvement in COVID-19 infection is not entirely clear but it could be in part explained by the viral tropism in the kidney parenchyma. AKI in COVID-19 infection can be either by direct invasion of the virus, or as a consequence of immunologic response. Diverse studies have focused on the effect of COVID-19 on glomerulonephritis (GN) patients or the ‘novo’ GN; however, the effect of COVID-19 in acute tubulointerstitial nephritis (ATIN) has been scarcely studied. In this article, we present five cases with different spectrums of COVID-19 infection and ATIN that may suggest that recent diagnosis of ATIN is accompanied with a worse clinical prognosis in comparison with long-term diagnosed ATIN. Novel coronavirus disease infection was declared a global pandemic in March 2020 and since then has become a major public health problem to both out-and inpatients (1) . COVID-19 infection presents from its asymptomatic form to pneumonia associated with multiple organ failure, and death. The prevalence of COVID-19 infection and acute kidney injury (AKI) varies between 20-80% of cases, and this may be in part ascribed to the clinical characteristics of patients and their geographical location (2, 3) . Several publications have focused on the pathogenesis of kidney injury in the setting of COVID-19 (2) . AKI appears to have different etiologies such as prerenal azotemia, tubular injury, cytokine storm, microangiopathy and virus-mediated injury (4) (Figure 1 ). The pathophysiology of renal involvement in COVID-19 infection is not entirely clear, but it seems that kidney injury could result from direct damage to the parenchyma, sepsis, thrombotic phenomena and treatment complications (1, 2, 4) . In addition, other authors consider that kidney disease is more likely related to the systemic and pro-inflammatory effect of sepsis instead of direct damage from viral-like particles in the kidney parenchyma (5) . Taking this into consideration, in our opinion, the mechanisms of AKI secondary to COVID-19 are mainly multifactorial, involving both direct and indirect viral damage. Histologically, COVID-19 infection develops a wide spectrum of glomerular and tubular diseases, with acute tubular necrosis being the most frequent kidney lesion and focal and segmental collapsing glomerulonephritis (GN) the most common glomerulopathy (6, 7) . Whereas some authors have identified viral particles-like by electron microscopy or by in situ hybridization of RNA SARS-COV2 in the kidney with unknown clinical significance, other authors have not been able to identify SARS-COV2 viral particles in COVID-19 patients with associated kidney injury (7, 8, 9) . Acute tubulointerstitial nephritis (ATIN) is a common cause of AKI and presents with inflammatory infiltrates and edema in histological samples. Pharmacological exposure is the most frequent etiology; however, bacterial and viral infections are also important, accounting for 5-10% of cases (10) . High clinical suspicion is needed to diagnose ATIN since the initial phase of ATIN does not typically manifest with oliguric AKI and haematuria. A proper and fast diagnosis of ATIN is required because the disease is reversible when early corticosteroid treatment is started (2, 10) . ATIN patients started kidney function recovery within a few weeks and complete improvement of baseline kidney function after 5 to 8 weeks of steroid treatment. Maintenance of steroid treatment should be shortened to 2-3 months avoiding the secondary effects related to steroids (11) . Currently there is limited scientific literature on COVID-19 and ATIN in terms of its clinical course and short and long-term prognosis. In this article, we present five cases of COVID-19 infection and ATIN and review current evidence on AKI and COVID-19 infection. We performed a retrospective study of medical records of 60 patients with histological diagnosis of ATIN from January 2013 to November 2020. In these patients, we studied the prevalence of COVID-19 infection, clinical characteristics and prognosis from March to December 2020. In addition, we reviewed the published literature in PubMed up to July 19, 2021 . The search strategy included the terms "acute tubulointerstitial nephritis", "acute kidney injury and COVID", "COVID-19", "coronavirus", and "SARS-CoV2" without language or type of article restrictions. Of 60 patients with ATIN, 5 (8.3%) patients were diagnosed with COVID-19 ( Table 1 ). The characteristics of the 5 patients are detailed below: An 85-year-old woman with a history of scalp melanoma BRAF wild-type with pulmonary metastasis that was successfully treated with nivolumab and LAG-3 antibody who developed ATIN secondary to immunobiological agents in 2018. She was diagnosed with mild COVID-19 in April 2020 with a positive swab test performed in a hospice as screening without indication for hospital admission. Her renal function was stable and maintained after 3 and 6 months of follow-up. A 64-year-old man without prior renal impairment presented with acute shortness of breath and fever. He was admitted and diagnosed with COVID-19 infection. Twenty-four hours after admission, he developed severe COVID-19 pneumonia and AKI Akin stage 3 with proteinuria/creatinine ratio of 1.7g/g (albumin/creatinine 0.13g/g) without hematuria that required orotracheal intubation and continuous veno-venous hemodiafiltration. During his admission, antibiotic therapy with ceftriaxone, nebulized tobramycin, and linezolid was started due to pneumonia secondary to methicillin-resistant Staphylococcus aureus (MRSA). Kidney biopsy was performed and ATIN probably associated to COVID-19 infection was diagnosed. Steroid treatment was initiated with methylprednisolone pulses for 3 days followed by maintenance steroid therapy (mg/kg) with complete recovery of renal function and improvement of proteinuria at 3 months of follow-up (See Figure 2 ). An 82-year-old woman with a past medical history of hypertension, diabetes mellitus, and mixed anxiety-depressive disorder was admitted with AKI Akin stage 3 due to ATIN An 86-years-old man with a past medical history of hypertension, diabetes mellitus, atrial fibrillation, and chronic kidney disease stage 3b A3 was admitted with deterioration of kidney function due to ATIN secondary to proton-binding inhibitors on december 2020. Eight-days after his admission, he developed a nosocomial COVID-19 infection without oxygen requirement or respiratory involvement. After two weeks of steroids initiation, kidney function improved and reached basal serum creatinine levels at three months. In this article, we described five adverse drugs reactions and viral load (21) . Hypouricemia with uricosuria has also been identified as a risk factor for severity and respiratory failure (21) . Collapsing glomerulopathy is the most common glomerular disease, especially in Afro-American people with high-risk genotypes of apolipoprotein L1 (APOL1) (22) . To date, 24 cases of acute kidney injury with nephrotic syndrome and COVID-19 infection associated with APOL1 have been described (20, 22) . The pathophysiology still remains uncertain, although it is believed that viral involvement resembles other infections such as HIVassociated nephropathy, Epstein-Barr virus, cytomegalovirus, and Parvovirus B19 ascribed to cytokine storm release and podocyte involvement due to upregulated viral infection that results in an inflammatory "second hit" (23, 24) . Furthermore, León-Román et al. infection is not fully clarified despite the fact that many studies associate it with sepsis (25) . lupus erythematosus, antiphospholipid syndrome, typical and atypical hemolytic uremic syndrome, and thrombotic thrombocytopenic purpura (26) . COVID-19 infection seems to involve complement and platelet activation without observing platelet consumption. One of the suggested mechanisms for complement activation has been the binding of the nucleocapsid protein to a protease of the lectin-dependent complement pathway (26) . To date, few cases of acute interstitial nephritis have been described as a result of SARS-CoV2 viral damage and/or pharmacological treatment (20) (21) (22) (23) (24) (25) (26) (27) . For this reason, the prognosis of COVID-19 in ATIN patients is unknown in accordance with the scarcity of literature data. Our study has some limitations. Firstly, the retrospective character of the study, and secondly the small sample size (n=5) of ATIN patients with COVID-19 infection. However, we would like to highlight the importance that this study was performed in one of the centers with highest COVID-19 incidence in Spain, and is the reference center for extracorporeal membrane oxygenation (ECMO) in Barcelona (28) . Our COVID-19 and the kidney: what we think we know so far and what we don't Outcomes Among Patients Hospitalized with COVID-19 and Acute Kidney Injury Acute kidney injury in patients hospitalized with COVID-19. Kidney International Swaminathan S; COVID-19 and ACE2 in Cardiovascular, Lung, and Kidney Working Group. 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