key: cord-0767940-vhd7ahsc authors: Ng, Jia H.; Bijol, Vanesa; Sparks, Matthew A.; Sise, Meghan E.; Izzedine, Hassane; Jhaveri, Kenar D. title: Pathophysiology of Acute Kidney Injury in Patients with COVID-19 date: 2020-10-20 journal: Adv Chronic Kidney Dis DOI: 10.1053/j.ackd.2020.09.003 sha: 337da78185869021c13a013a390c9f002282bd8b doc_id: 767940 cord_uid: vhd7ahsc Acute kidney injury (AKI) is common among hospitalized patients with Coronavirus Infectious Disease 2019 (COVID-19), with the occurrence of AKI ranging from 0.5% to 80%. The variability in the occurrence of AKI has been attributed to the difference in geographic locations, race/ethnicity, and severity of illness. AKI among hospitalized patients is associated with increased length of stay and in-hospital deaths. Even patients with AKI who survive to hospital discharge are at risk of developing chronic kidney disease (CKD) or end-stage kidney disease (ESKD). An improved knowledge of the pathophysiology of AKI in COVID-19 is crucial to mitigate and manage AKI and to improve the survival of patients who developed AKI during COVID-19. The goal of this article is to provide our current understanding of the etiology and the pathophysiology of AKI in the setting of COVID-19. Acute kidney injury (AKI) has been reported to be a common complication among hospitalized patients with Coronavirus Infectious Disease 2019 (COVID-19) disease, with the occurrence of AKI ranging from 0.5% to 80%. [1] [2] [3] [4] [5] The understanding of the pathophysiology of AKI in the Patients with COVID-19 often present with fever, volume depletion, and shortness of breath. Additionally, around 10% of patients with COVID-19 experienced at least one gastrointestinal symptom (nausea, vomiting or diarrhea), 6, 7 all of which contributed to fluid losses. In a study from New York, 66% of the patients with AKI had a urine Na of <35 mmol/L, suggestive of a prerenal state or low effective arterial blood volume from heart failure or liver cirrhosis. 2 Based on a study by Mohamed et al., pre-renal azotemia accounted for 9-10% of AKI in patients with COVID-19. 8 While the majority of the cases of prerenal AKI were from hypovolemia, some cases of AKI resulted from acute cardio-renal syndrome associated with COVID- 19. 9 Acute Tubular Injury J o u r n a l P r e -p r o o f Evidence to date shows that the vast majority of AKI in patients with COVID-19 were related to acute tubular injury (ATI). From a single center study in the United States (US), 8 greater than 60% of AKI was attributed to acute tubular injury either from ischemic or toxic tubular injury. Several publications examining native kidney biopsy and autopsy have demonstrated acute tubular injury as the most common pathologic finding in patients with COVID-19 and concomitant AKI. [10] [11] [12] [13] [14] Acute tubular injury may occur in the setting of prolonged volume depletion and hemodynamic states that reduce kidney perfusion. In severe COVID-19, viral infection in type II alveolar cells results in immune cell recruitment, which produce an abundance of cytokines that can lead to circulatory collapse. 15 From our background knowledge of sepsis-induced AKI, the exact pathophysiology of this illness is not known. However, it is generally accepted that it results from multi-factorial injury. This form of AKI has components of ischemia-reperfusion injury, direct inflammatory injury, coagulation and endothelial cell dysfunction, and apoptosis. 16 Table 1 and Figure 2 summarize the kidney biopsy findings in patients with COVID-19 and AKI that have been published at the time of this writing (September 2020). Based on this series, the median age of nine patients who developed acute tubular injury was 63 years (interquartile range IQR 54, 69). The median peak serum creatinine was 4.8 mg/dL (IQR 4.4, 5.8) . Two out of the nine patients died; and among those who survived, one patient remained on dialysis upon discharge. It is important to note that kidney biopsies are typically not done for patients with a clinical diagnosis of acute tubular injury. Thus, the kidney biopsy series that have been published reflect "for-cause" biopsies and may not reflect the full extent of acute tubular injury in COVID- 19. Hyperinflammation has been associated with COVID-19. 15 The type of hyperinflammation observed in patients with severe COVID-19 is similar to hemophagocytic syndrome-related cytokine release. Secondary hemophagocytic lymphohistiocytosis (sHLH) is an underrecognized, hyperinflammatory syndrome characterized by a fulminant and fatal J o u r n a l P r e -p r o o f hypercytokinemia with multiorgan failure. In adults, secondary hemophagocytic lymphohistiocytosis is most commonly triggered by viral infections and occurs in 3.7-4.3% of patients with sepsis and is sometimes referred to as macrophage activation syndrome. 17, 18 Cardinal features of this syndrome include unremitting fever, cytopenias, and hyperferritinemia. Pulmonary involvement such as acute respiratory distress syndrome (ARDS) occurs in approximately 50% of patients with secondary hemophagocytic lymphohistiocytosis. 19 A cytokine profile resembling this hemophagocytic syndrome is associated with COVID-19 severity, characterized by increased interleukin (IL)-2, 6, 7, granulocyte-colony stimulating factor, interferon-γ inducible protein 10, monocyte chemoattractant protein 1, macrophage inflammatory protein 1-α, and tumor necrosis factor-α. Many studies have now shown high ferritin levels as a predictor of mortality. 20 The incidence of AKI during hemophagocytic lymphohistiocytosis is high (62%, [59/95] The pro-inflammatory IL-6 is thought to be the principal cytokine that drives hyperinflammation in many of these syndromes. Among patients with COVID-19, the plasma concentration of IL-6 has been shown to be increased in those with ARDS. 23 Cytokine overproduction is also thought to mediate a crosstalk between the lung and kidney leading to bidirectional damage. 24 Injured kidney tubular epithelium leads to an upregulation of IL-6. Human and animal studies have shown increased levels of serum IL-6 in patients with AKI, and this was associated with higher alveolar-capillary permeability and pulmonary hemorrhage. 25, 26 ARDS has been shown to induce kidney medullary hypoxia, which may act as an additional insult to tubular epithelial cells. 24 J o u r n a l P r e -p r o o f Tubular injury from rhabdomyolysis 27 and a severe form of hyperinflammation 28 should be considered in the differential diagnosis of AKI in patients with COVID-19. Patel et al 28 reported a series of patients with hypermetabolism-related AKI, with striking elevations in uric acid, phosphorus, and potassium levels; lactate-negative anion gap; metabolic acidosis; and drastic decreases in serum albumin levels. There was no evidence of tumor lysis syndrome or rhabdomyolysis. While severe acute tubular injury associated with sepsis can present with rapid AKI, such hypercatabolic states in COVID-19 can also be the cause of severe prerenal azotemia and tubular injury. Proximal tubular damage leading to AKI along with several electrolyte disorders has been described as well. In a cohort of 49 patients requiring hospitalization in a large academic hospital in Belgium, the investigators found evidence of proximal tubule dysfunction in a subset of patients with COVID-19, as attested by low-molecular-weight proteinuria (70-80%), neutral aminoaciduria (46%), and defective handling of uric acid (46%) or phosphate (19%). 29 Among these 49 patients, 22% developed AKI. At the structural level, 6 kidney autopsy samples from patients with COVID-19 showed prominent tubular injury, including in the initial part of the proximal tubule, with loss of brush borders, epithelial cell necrosis, collections of intraluminal debris, and a marked decrease in the expression of megalin in the brush border. 29 Interstitial disease was not as common as tubular injury, observed only in 2 out of the 6 patients 29 . Glomerular diseases have been reported in association with COVID-19. Collapsing glomerulopathy (CG) is the most common form of glomerular disease, but other forms have been reported with variable frequencies. 27, [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] Collapsing glomerulopathy has emerged as a distinct pathology associated with SARS-CoV-2 infection, which seems to specifically affect individuals of African ancestry who have high risk APOL1 genotypes (G1/G1, G1/G2, or G2/G2). To date, 24 cases of collapsing glomerulopathy have been published in patients with COVID-19. A total of 18 of 22 of the cases mentioned had APOL1 polymorphisms (12/18 with homozygous G1/G1 and 6/18 with heterozygous G1/G2). All cases presented with AKI or nephrotic syndrome; 23/24 (96%) patients were of Black race or of African or African American heritage and 1 patient was of Asian (Indian) origin. Most of the cases 19/24 (79%) were from the US and remaining from Europe, whereby 10/24 (42%) patients remained dialysis-dependent and 20/24 (83%) patients were alive at the time of this writing (September 2020). Among those who were off of dialysis, the median serum creatinine upon discharge was 2.9 mg/dL (IQR 2.6, 3.6). The pathogenesis of COVID-19-associated collapsing glomerulopathy is unclear. Collapsing glomerulopathy is a histopathological feature that has been associated with other viral infections; most characteristically seen in HIV-associated nephropathy (HIVAN), but also seen in Ebstein-Barr virus, cytomegalovirus and parvovirus B19. 40 How different viral infections would result in similar histopathological findings is worth exploring. Some have proposed a direct viral involvement in collapsing glomerulopathy, particularly in HIVAN 41 and parvovirus B19 42 , others suggest that this may result from the systemic response to infection and hyperinflammation. 43 In COVID-19, the inflammatory milieu may trigger or exacerbate immune-mediated diseases in predisposed patients. 6, 27, 30 Viral-induced hyperinflammation causes massive release of J o u r n a l P r e -p r o o f granulocyte colony-stimulating factor, various interleukins, and interferons. 20, 44, 45 APOL1 expression is upregulated by viral infections and other inflammatory diseases that activate interferons and toll-like receptor-3. 46 Viral infections stimulate host interferon production, and interferon is a potent stimulus to APOL1 gene expression. 46 Thus, in individuals with high risk APOL1 genotypes (which are most common in persons of West African ancestry), SARS-CoV-2 infection and the resulting hyperinflammation may act as a "second hit" that leads to podocyte dysregulation, injury and collapsing glomerulopathy. 47 Other glomerular diseases, such as anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, 27, 48, 49 anti-glomerular basement membrane (GBM) disease 50 and IgA vasculitis without nephropathy 51 have been reported in patients with COVID-19. A total of 9 cases of ANCA vasculitis and anti-GBM disease have been reported; and 5 of 9 required dialysis. All 9 patients received treatment with various immunosuppressive therapy and are alive off dialysis at the time of discharge. A single case of immunoglobulin A (IgA) nephropathy has been reported. 52 Other glomerular diseases including membranous nephropathy and minimal change disease have been reported as well. 30 There are two possible explanations for seeing the variety of glomerular diseases in patients with COVID-19. One can postulate a predilection for a specific glomerular pathology for these patients and SARS-CoV-2 acted as a "second hit". Alternately, these processes could have been unrelated to SARS-CoV-2 and could represent incidental findings. The development of coagulopathy and disseminated intravascular coagulation (DIC) is a devastating complication in patients with sepsis that is associated with increased mortality. 53 The pathophysiology of DIC is complex and thought to occur by immune over-activation and disordered coagulation leading to pathologic organ dysfunction. 54 In patients with severe COVID-19, overall mortality is higher among those who developed DIC; 71.4% of non-survivors met the International Society on Thrombosis and Haemostasis (ISTH) diagnostic criteria for DIC whereas only 0.6% of survivors met criteria for DIC. 55 One case of TMA has been described in patients with COVID-19, with the kidney biopsy showing diffuse cortical necrosis and widespread glomerular microthrombi. 55 However, recent evidence suggests that signs and symptoms of severe COVID-19 resemble the pathophysiology and phenotype of complementmediated thrombotic microangiopathies (TMA), 27,56,57 rather than sepsis-induced coagulopathy or DIC. To our knowledge and at the time of this writing in September 2020, no cases have been reported of kidney vein thrombosis associated with COVID-19; although kidney arterial thrombosis leading to kidney infarction has been reported. 58, 59, 60 Certain treatment-related causes of AKI in patients with COVID-19 such as the use of antiviral agents leading to tubulointerstitial diseases, 61, 62 and two cases of biopsy proven vitamin C related oxalate nephropathy 63 have also been reported. In addition, kidney infarction has been postulated as a cause of AKI. 30, 60 Trials of multiple molecules such as lopinavir/ritonavir, nucleoside analogues, remdesivir, tenofovir, chloroquine phosphate or hydroxychloroquine J o u r n a l P r e -p r o o f sulfate have been used in patients with COVID-19. Moreover, the use of antibiotics, many of which have been implicated in AKI, are commonly given during hospitalization for COVID-19. 64 Thus, treatment-related complications need to be considered when determining the etiology of AKI. In one of the first autopsy series published from China, 26 autopsies were performed for patients with COVID-19. 14 These cases were all rapid autopsies with a post-mortem interval of 6 or fewer hours, which reduces autolytic artifacts within tissue. All cases in the series showed mild to severe acute tubular injury. Acute tubular injury was characterized by a loss of the proximal tubular brush borders, vacuolar degeneration (non-isometric in most cases), frank epithelial cell necrosis (4 cases), pigmented granules within tubular cytoplasm (4 cases), and pigmented casts in tubular lumens (3 cases). There was evidence of glomerular ischemia in 7 cases, with 3 of the cases showing fibrin thrombi within the glomerular capillary loops. This was rarely associated with an overlying epithelial cell proliferation (pseudocrescent formation). No proliferative changes were identified within the glomeruli, such as endocapillary hypercellularity or true crescents. In another retrospective study of 81 patients in a single center in China, a total of 41 (50.6%) patients experienced AKI. Limited autopsy of 10 patients showed pathologic findings consistent with acute tubular injury. 4 More recently, several kidney autopsy series from New York were published. Combined data from Northwell Health and Columbia University Medical Center showed that 72% (31/43) in the autopsies were acute tubular injury with varying degrees of severity. 12 There was no evidence of glomerulonephritis, vasculitis, thrombotic microangiopathy, or classic viral nephropathy. Another autopsy series from NYU in the United States of 9 patients was analyzed. 65 Other than findings consistent with acute tubular injury, the authors also reported platelet-rich fibrin 29 On the other hand, data from Northwell Health and Columbia University Medical Center in New York, describing a total of 52 autopsy cases and 29 kidney biopsies from living patients, report negative results by immunohistochemistry or in situ hybridization in all tested cases. 12, 13, 27, 30 In the Columbia series, rare tubular epithelial staining (<1 in 200 cells) with low-intensity dot-like positivity was described in many cases, in the setting of a high background staining, and substantially less intense than the staining in lung specimens from autopsies with COVID-19. The authors conclude that the rare equivocal staining may represent nonspecific staining or low viral abundance. Viral-like particles were commonly identified on electron microscopy, but unequivocal features of coronavirus were not seen, as previously described. 69, 71 An autopsy series from Washington state in the US included 14 patients, with focally positive immunohistochemistry findings in 2 out of 4 tested kidney samples; they also describe viral-like particles in 3 of 3 cases with electron microscopy examination. 74 The various methods used to detect the presence of SARS-CoV-2 as reported by these studies are summarized in Table 2 . SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) to gain entry to the host cell. 75 Access to the cellular ultrastructure needed for viral replication is also dependent upon proteases such as transmembrane serine protease 2 (TMPRSS2) and furin. 76 ACE2 is expressed in the kidney and is localized to the apical brush border of proximal tubular cells with J o u r n a l P r e -p r o o f some expression in the distal tubule, interlobular arteriole endothelium, and vascular smooth muscle. 77, 78 Lower expression of ACE2 is found in the glomerulus and is predominantly seen in podocytes. Some have postulated that the virus could enter the kidney via ACE2. However, SARS-CoV-2 uses TMPRSS2 in addition to ACE2 in order to be primed to gain entry into host cells. TMPRSS2 is primarily expressed in the distal nephron as opposed to the proximal tubule where ACE2 is expressed. 79 In summary, although direct viral infection of the kidney is possible, it is certainly not a common or even widespread finding reported ( Table 2 ). In fact, SARS-CoV-2 is detected uncommonly by immunohistochemistry or in situ hybridization. Electron microscopy is a suboptimal method of detection as it relies solely on morphology and the particle size, leaving room for confusion with normal cellular structures. Treatment and management of patients with COVID-19-associated AKI is generally similar to patients with AKI associated with septic shock. Conservative management of volume overload, metabolic acidosis, and hyperkalemia can be attempted before considering initiation of dialysis. In cases of collapsing glomerulopathy, TMA and other glomerular diseases, careful management of COVID-19 and specific glomerular pathology might be prudent. Shaikh et al. discusses the management of COVID-19-associated AKI in this issue of ACKD. 84 Other recent publications have reported on the association of AKI with in-hospital death among those hospitalized with COVID-19. 1,3,85 Early reports from Wuhan, China, found that the risk of death was increased with AKI. 86 Based on a recent publication from New York of approximately 9600 hospitalized COVID-19 patients, the risk of in-hospital death was increased with AKI even after adjusting for baseline demographic, comorbid conditions and illness severity (HR 3.4 for AKI-not requiring dialysis, HR 6.4 for AKI-requiring dialysis). 87 Dashed line -the association is less well understood. Dark green box and bolded font -acute tubular injury is the predominant mechanism for acute kidney injury. 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