key: cord-0855264-tbfpm88d authors: Ng, Jia H; Zaidan, Mohamad; Jhaveri, Kenar D; Izzedine, Hassan title: Acute tubulointerstitial nephritis and coronavirus date: 2021-07-10 journal: Clin Kidney J DOI: 10.1093/ckj/sfab107 sha: 2d9195044c9f5de8541aa8025069cd40e9cb5ed3 doc_id: 855264 cord_uid: tbfpm88d Coronavirus disease 2019 (COVID-19) is an ongoing pandemic that to date has spread to >100 countries. Acute kidney injury is not uncommon with this disease. The most common kidney biopsy finding is acute tubular injury. Glomerular diseases such as collapsing glomerulopathy and vasculitis, and thrombotic microangiopathy have been reported. Viral inclusion particles with distinctive spikes in the tubular epithelium and podocytes, and endothelial cells of the glomerular capillary loops, have been visualized by electron microscopy by some but disputed by others as non-viral structures. Interstitial infiltrates have not commonly been described in the published kidney biopsy series from patients with COVID-19. Medications used to treat COVID-19 can lead to interstitial nephritis, but very few have been reported. In summary, interstitial kidney disease is a rare finding in COVID-19. MERS is still considered to be an ongoing epidemic but appears to be limited to its area of origin [8, 9] . SARS-CoV-2/coronavirus disease 2019 (COVID- 19) is an ongoing pandemic that to date has spread to >100 countries (World Health Organization 2020). The estimated case fatality rates (CFRs) for COVID-19 are to be around 2.3% [10] . Nonetheless, despite its lower CFR, COVID-19 has now caused orders of magnitude more deaths than SARS and MERS combined [11] . Viral nephropathy may be caused by viruses themselves or virus-induced immune mechanisms. This article summarizes current evidence on tubulointerstitial kidney disease during CoVs infection. Epidemiology Kidney involvement of human CoV was noticed when the SARS-CoV epidemic occurred in the early 2000s. AKI was reported in 6.7% of 536 patients with SARS-CoV [12] and was an independent risk factor predicting mortality [13] SARS-CoV patients developed AKI at a median duration of 20 days from the onset of viral infection [14] . The detection of polymerase chain reaction fragments of coronavirus in urine from 21% to 50% of SARS patients between the second and the third week of the viral infection implied a possibility of kidney tropism of the CoV [15] . AKI appears to be frequent in the context of MERS. In a Saudi cohort, 30 out of 70 MERS patients (42.9%) developed AKI during the course of their illness [16] . Among critically ill MERS patients, AKI was reported to develop in 75% of them [13, 17] . Progressive impairment of renal function and AKI start 9-12 days after symptom onset among MERS patients, compared with a median of 20 days for SARS patients [12, 17, 18] . However, despite the presence of viral particles in renal proximal tubular epithelial cell, no evidence of concurrent tubulointerstitial nephritis was identified [19] . AKI is a frequent complication of SARS-CoV-2 (Table 1) and is associated with mortality especially when dialysis is required . Assessment of data from major published cohorts on COVID-19, combining results from intensive care unit (ICU) admissions with non-ICU admission, reveals an overall AKI incidence of around 4.2% [32, 42, [49] [50] [51] [52] . Among the nonsurvivors, the incidence of AKI is $30% and renal replacement therapy (RRT) is required in 19.5%. Comparatively, in the SARS outbreak in 2003, the incidence of AKI was around 6.7% and multivariate analysis showed AKI as a significant independent risk factor for predicting mortality [relative risk: 4.057; 99% confidence interval (CI): 1.461-11.27; P < 0.001] [12] . In China, the reported incidence of AKI in hospitalized patients with COVID-19 ranged from 0.5% to 29% [31, 32, 35, 53] and occurred within a median of 7-14 days after admission [31, 53] . Studies from the USA have reported much higher rates of AKI. In a study of nearly 5500 patients admitted with COVID-19 in a New York City hospital system, AKI occurred in 37%, with 14% of the patients requiring dialysis [39] . About one-third were diagnosed with AKI within 24 h of admission in this study. Of note, these rates are much higher than those reported during the SARS-CoV epidemic [12] . AKI occurred at much higher rates in critically ill patients admitted to New York City hospitals, ranging from 78% to 90% [19, [37] [38] [39] 54] . Of 257 patients admitted to ICUs in a study from New York City, 31% received RRT [38] . In a multicentre cohort study of 3099 critically ill adults with COVID-19 admitted to ICUs at 67 hospitals across the USA, AKI-RRT is common among critically ill patients with COVID-19 (20.6%) and is associated with a hospital mortality rate of >60%. Among those who survive to discharge, 33.8% still depend on RRT at discharge and 18.1% remain RRT dependent 60 days after ICU admission. Patient-level risk factors for AKI-RRT included chronic kidney disease (CKD), men, non-White race, hypertension, diabetes mellitus, higher body mass index, higher D-dimer and greater severity of hypoxaemia on ICU admission. Predictors of 28-day mortality in patients with AKI-RRT were older age, severe oliguria and admission to a hospital with fewer ICU beds or one with greater regional density of COVID-19 [40] . In an observational retrospective cohort study including 9657 patients admitted with COVID-19 limited to the New York metropolitan area during the peak of the COVID-19 pandemic (between 1 March 2020 and 27 April 2020), AKI in hospitalized patients with COVID-19 was associated with significant risk for death. Among patients with AKI Stages 1-3 who survived, 74.1% achieved kidney recovery by the time of discharge. Among those with AKI receiving dialysis who survived, 30.6% remained on dialysis at discharge, and pre-hospitalization CKD was the only independent risk factor associated with needing dialysis at discharge (adjusted odds ratio: 9.3; 95% CI: 2.3-37.8) [41] . Case reports and autopsy series have revealed that most patients with COVID-19-associated AKI have evidence of prominent acute tubular necrosis and diffuse erythrocyte aggregation, specific dysfunction of the proximal tubules (loss of the brush border, intratubular debris and reduced expression of the endocytosis receptor megalin in the brush border), endothelial damage and capillary occlusions, tubules and glomerular complement complex deposit [55] [56] [57] [58] [59] . More recent findings support SARS-CoV-2 kidney tropism. A higher SARS-CoV-2 viral load in urine sediments from COVID-19 patients correlated with increased incidence of AKI and mortality [60] . A mild associated interstitial infiltrate may be present [60] . Other biopsy findings have included collapsing glomerulopathy associated with African ancestry and a high-risk APOL1 genotype [59, 61, 62] , thrombotic microangiopathy and diverse underlying kidney diseases [56, 59, [63] [64] [65] . Kidney infarction has also been reported [66] (Table 2) . Viral inclusion particles with distinctive spikes in the tubular epithelium and podocytes, and endothelial cells of the glomerular capillary loops, have been visualized by electron microscopy [57, 58, 67] and may support this possibility, although the clinical significance of this remains unknown [68, 69] . The demonstration of lymphocytic endothelialitis in the kidney, in addition to viral inclusion particles in glomerular capillary endothelial cells, suggests that microvascular dysfunction is secondary to endothelial damage [67] . Other potential etiologies of AKI common to critical illness presentations, including acute respiratory distress syndrome, rhabdomyolysis, volume depletion and interstitial nephritis, all remain relevant in patients with COVID-19 [70] . Acute interstitial nephritis (AIN) is not a rare cause of AKI but it remains a Cinderella among other causes, being underrecognized and underdiagnosed despite the fact that it is a serious reversible disease that can cause CKD and end-stage renal disease . The same probably applies to COVID-19. AIN is a disease of tubular dysfunction with insidious onset that usually starts as non-oliguric acute renal failure with signs of tubulointerstitial damage that are present but rarely dominate, therefore high clinical suspicion is necessary for timely diagnosis at its reversible stage and early treatment that highly impacts its outcome. AIN, as one of the differential diagnoses of kidney injury in COVID-19 patients, should therefore be important part of the equation when deciding on medications including steroids. Although AIN remains uncommon during COVID-19 infection (Table 3 ) [64, [71] [72] [73] [74] , several mechanisms may explain such findings ( Figure 1 ). Specific interstitial infiltration. Interstitial infiltrates have not commonly been described in the published kidney biopsy series from patients with COVID-19 [56, 58, 63] . SARS-CoV-2 has been detected in a kidney allograft [71] associated with a mononuclear cell infiltrate, indicating that the virus is able to enter renal parenchyma and may cause interstitial nephritis. Recent post mortem histopathological analyses showed positive immunostaining with SARS-CoV nucleoprotein antibody in tubules, which supports these findings [57] . It is important to pay attention to low molecular weight proteinuria (Pu) and ionic disorders, as they precede AKI and tubulointerstitial involvement [75] . Werion et al. [76] established that SARS-CoV-2 causes specific manifestations of proximal tubule dysfunction as attested by low molecular weight Pu (70-80%), neutral aminoaciduria (46%) and defective handling of uric acid (46%) or phosphate (19%), but not of glucose, corresponding to a partial renal Fanconi syndrome. Proximal tubule dysfunction was independent of pre-existing comorbidities, nephrotoxic medications or viral load. At the structural level, kidneys from patients with COVID-19 showed prominent tubular injury, including in the initial part of the proximal tubule, with brush border loss, acute tubular necrosis, intraluminal debris and a marked decrease in the expression of megalin in the brush border [76] . Among features of proximal tubule dysfunction, hypouricaemia with inappropriate uricosuria was independently associated with disease severity and with a significant increase in the risk of respiratory failure requiring invasive mechanical ventilation. The molecular mechanisms accounting for such specific defects remain unknown [76] . Even though studies argue against SARS-CoV-2 nephropathy [77] , we know that there are many cases of AIN caused by infections remote to the kidney (Legionella, leptospirosis and streptococcal organisms), and that might also be a case with SARS-CoV-2. Finding virus or its particles within kidney does not necessarily mean direct clinical-pathological connection with AKI, and vice versa. Medication-induced nephrotoxicity is a relatively common cause affecting the tubulointerstitial compartment [78, 79] . However, despite patients with severe COVID-19 in the ICU likely receive multiple medications, drug-induced AIN remains uncommon in this setting. Only case reports of drug reaction with eosinophilia and systemic symptoms syndrome associated with hydroxychloroquine or azithromycin [80] and a drug-induced granulomatous [72] have been reported in patients with COVID-19, with a good response to corticosteroid therapy. Furthermore, specific therapeutic treatments for COVID-19 itself such as the use of antiviral agents can potentially induce tubulointerstitial diseases [81] [82] [83] [84] . Thus, treatment-related complications need to be considered when determining the etiology of AKI. Other disease-associated AIN Several diseases reported to be associated with COVID-19, such as secondary haemophagocytic lymphohistiocytosis [85] and autoimmune haemolytic anaemia [86] [87] [88] , can induce AIN [88, 89] . 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