key: cord-1046031-6nnk0qxc
authors: Sharma, Purva; Ng, Jia H; Bijol, Vanesa; Jhaveri, Kenar D; Wanchoo, Rimda
title: Pathology of COVID 19 associated acute kidney injury
date: 2021-01-24
journal: Clin Kidney J
DOI: 10.1093/ckj/sfab003
sha: 593bc55c1fb9a8bd415fc803c8475ff14244b7f0
doc_id: 1046031
cord_uid: 6nnk0qxc

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%. An improved knowledge of the pathology of AKI in COVID-19 is crucial to mitigate and manage AKI and to improve the survival of patients who develop AKI during COVID-19. In this review, we summarize the published cases and case series of various kidney pathology seen with COVID-19. Both live kidney biopsies and autopsy series suggest acute tubular injury as the most commonly encountered pathology. Collapsing glomerulopathy and thrombotic microangiopathy are other encountered pathologies noted in both live and autopsy tissues. Other rare findings such as ANCA vasculitis, Anti GBM disease, and podocytopathies have been reported. Although direct viral infection of the kidney is possible, it is certainly not a common or even widespread finding reported at the time of this writing (November 2020).

A novel coronavirus named Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS- was identified in December 2019 in China. This virus causes coronavirus disease 2019 COVID-19, which is characterized by a diffuse alveolar damage leading to an acute respiratory distress syndrome (ARDS) (1) . Organs other than the lungs may be affected, including the kidneys. The incidence of Acute kidney injury (AKI) in hospitalized patients with COVID-19 disease has been reported to range from 0.5% to 80% (2) (3) (4) . In the United States, AKI among hospitalized patients with COVID-19 may range between 28% and 46%, with high risk for in-hospital mortality (5, 6) . Patients who develop AKI have a worse outcome as compared to those with normal kidney function (5) .

In this review, we first discuss the controversy behind SARS-CoV-2 and its role in direct kidney infection, then classify AKI in COVID-19 based on the pattern of injury and describe all published histopathological changes in detail. Lastly we describe biopsy findings in kidney transplant recipients. Pathophysiology of COVID-19 related AKI is discussed in a separate manuscript in this issue of the journal.

Certain viral infections of the kidney, including BK polyomavirus, adenovirus, and cytomegalovirus, are typically associated with viral cytopathic effect, i.e., nuclear or cytoplasmic inclusions and sometimes extensive tissue necrosis and inflammation. None of these changes have been reported in biopsy and autopsy series describing kidney pathology in COVID-19 (7) (8) (9) (10) (11) (12) . From the early studies it has become apparent that the SARS-CoV-2 virus is not associated with such obvious signs of direct viral infection, but its presence in the kidney has become a subject of controversy. Initial autopsy reports from China included ultrastructural evidence of viral particles and positive immunofluorescence staining for SARS-CoV-2 nucleoprotein, but these studies were performed in a portion of cases and in some cases with negative results (13) . Several other studies followed with variable results. Some reported positive identification of viral particles by electron microscopy but with negative results when using more specific tests, like RT-PCR (14, 15) . Others showed a detectable SARS-CoV-2 viral load in all kidney compartments examined by RT-PCR, in situ hybridization, and indirect immunofluorescence with confocal microscopy (16) (17) (18) . On the other hand, data from large autopsy and biopsy series from Columbia University and Northwell Health in NY and a multicenter biopsy series, report negative results by immunohistochemistry or in situ hybridization in all tested cases (8) (9) (10) (11) (12) . The Columbia group reported a low-intensity dot-like staining of tubule epithelial cells in many cases and this was interpreted as non-specific or suggestive of low level viral abundance, particularly when contrasted to the intense staining in lung specimens from autopsies with COVID-19 (9, 11) . Absolute certainty in viral particle identification by electron microscopy is very challenging because it is primarily based on particle morphology and size. Viral-like particles of SARS-CoV-2 were identified on electron microscopy in several studies, but these findings have been strongly challenged by others who proposed that these ultrastructural findings most likely corresponded to intracellular components like clathrin-coated vesicles and multivesicular bodies (17, (19) (20) (21) ( Figure 1 ) Ultrastructural details in autopsy tissues can also be misinterpreted as coronavirus particles (7) . Most of these images lack sufficient ultrastructure for viral classification. Some could represent endoplasmic reticulum, some multivesicular bodies and some coated vesicles (21) . Although direct viral infection of the kidney is possible, it is certainly not a common or even widespread finding reported thus far. At the time of this writing(November 2020), SARS-CoV-2 is detected uncommonly by immunohistochemistry or in situ hybridization.

The percentage of patients with COVID-19 associated acute kidney injury who undergo a kidney biopsy remains low due to logistical reasons and infection risk. Most of the biopsies done are for indication only so true prevalence of pathological changes may still not be known.

Data on pathology of COVID-19 associated acute kidney injury is primarily derived from case reports and case series. While most published case reports discuss glomerular disease findings associated with COVID-19 (collapsing glomerulopathy), this might be a relative publication bias.

Of note, it is common to see more than one compartment of the kidney to be involved. We summarize all the kidney biopsy findings in patients with COVID-19 and AKI that have been published at the time of this writing (November 2020). The three most common kidney biopsy findings to date associated with COVID-19 are acute tubular injury (ATI), collapsing glomerulopathy (CG) and thrombotic microangiopathy (TMA). A recent review on this topic by our group summarizes the pathophysiology and the pathology associated with COVID19 related AKI (22) , but the data now has been updated in this review. Table 1 summarizes all commonly reported kidney biopsy pathology seen with COVID19. Table 2 summarizes the kidney related autopsy data from key manuscripts published in 2020. Supplemental Table gives details of individual cases for all related pathologies.

Evidence to date shows that the vast majority of AKI in patients with COVID-19 is related to ATI.

In clinical practice, based on history alone, ATI seems to be the most common finding in patients with COVID-19 and AKI (23) . Several publications examining native kidney biopsy and autopsy tissue have demonstrated acute tubular injury as the most common pathologic finding in patients with COVID-19 and concomitant AKI or proteinuria (9, 10) . In a multi center study of 17 patients, acute tubular injury was seen in 14 patients often in association with other glomerular and or endothelial changes (12) . In a case series of 10 patients with COVID 19 and AKI or proteinuria, acute tubular injury was demonstrated in all patients (10) . (Figure 2 ) Kudose et al reported acute tubular injury on the kidney biopsy, either as the primary finding or a secondary finding in 12 out of 17 patients with COVID 19 and AKI. (9) In some of these cases a direct correlation existed between risk factors such as hemodynamic instability and development of AKI. Presence of myoglobin casts and ATI has been reported in 2 patients who developed rhabdomyolysis in association with COVID 19 (9, 10) . 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 disease.

Proximal tubular damage with acute tubular injury has been described in patients with COVID- Autopsy data available from histologic evaluation of the kidneys in patients dying from COVID 19 has been notable for the presence of ATI and necrosis, which was the main factor correlating with AKI. (8, 11) . In one of the first autopsy series published from China, 26 autopsies were performed for patients with COVID-19.(13) These cases were all rapid autopsies with a postmortem 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). In another retrospective study of 81 patients in a single center in China, a total of 41 (50.6%) patients experienced AKI (25) . In that study, they mention a limited autopsy of 10 Table 2) Artefactual autolysis in autopsy specimens can be difficult to distinguish from acute tubular injury, hence more credence should be given to kidney biopsies for this diagnosis.

Several glomerular diseases have been described in association with COVID-19. It's difficult to ascertain if development of the glomerular disease is directly related to the SARS-COV2 infection or whether this infection acts as a "second hit" in patients who already have a predilection for glomerular pathology such as those with high risk APOL1 genotype. The other possibility is that this represents an incidental finding unrelated to the SARS-CoV-2 infection.

Evidence of nephrotic-range proteinuria and collapsing glomerulopathy has been reported in patients with COVID-19 (27, 28) . Diffuse tubuloreticular inclusions called "interferon footprints" have been described in glomerular endothelial cells, which may reflect SARS-CoV-2-induced excessive production of cytokines including interferon. The most common glomerular disease noted with COVID-19 is collapsing glomerulopathy (CG).

CG has emerged as a distinct pathology associated with SARS-CoV-2 infection (Figure 3) , which seems to specifically affect individuals of African ancestry who have high risk APOL1 genotypes (G1/G1, G1/G2, or G2/G2). To date, 32 cases of collapsing glomerulopathy, either in isolation (28 cases) or in combination with other pathology findings (4 cases), have been published in patients with COVID-19 (9, 10, 12, 15, (28) (29) (30) (31) (32) (33) (34) (35) . A total of 21 cases mentioned had APOL1 polymorphisms (14 with homozygous G1/G1, 2 with homozygous G2/G2 and 5 with heterozygous G1/G2). All cases presented with AKI or proteinuria ; 30/32 (96%) patients were of Black race or of African or African American heritage, 1 patient was of Asian (Indian) origin and 1 of Hispanic origin. Of the 28 isolated COVID-19 associated CG, 64.2% required dialysis and 89% are alive at the time of this writing. Table 3 along with ATI and tubuloreticular inclusions (TRI). Interestingly, this patient was found to be homozygous for the high risk APOL1 genotype (G1/G1). Another case of MCD was described in a 52 year old woman presenting with nephrotic syndrome (12) . It is possible that the viral infection triggers a podocytopathy in some patients. Non-collapsing FSGS has also been described along with other pathologic findings likely representing underlying chronic disease (Supplemental Table and Table 3 )

Glomerulonephritis such as anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, (10, 41, 42) anti-glomerular basement membrane (GBM) disease (43) and IgA vasculitis with nephritis (44) have been reported in patients with COVID-19. Three cases of ANCA vasculitis and 6 cases of anti-GBM disease have been reported so far. Most patients had severe kidney impairment with 5 out of 9 patients requiring dialysis. All 9 patients received treatment with various immunosuppressive therapies and were alive with just one patient requiring dialysis at the time of discharge( Table 1) .

Two cases of membranous nephropathy have been described of which one was phospholipase A2 receptor antibody( PLA2R) positive by serum and another was PLA2R negative. (9) The authors postulated that since PLA2R is also present in the respiratory tract, it could be a potential source for antigen presentation to incite or potentiate anti-PLA2R autoimmune responses. This association could also be co-incidental.

Crescentic transformation of long standing pre-existing lupus nephritis presenting as acute kidney injury and nephrotic syndrome in a patient with severe COVID 19, was reported by Kudose et al. (9) . This may highlight the role of an inflammatory milieu to exacerbate preexisting immune mediated diseases in patients with COVID 19.

TMA has been described in patients with COVID 19 either as the primary finding or in combination with other pathologic features like acute tubular necrosis and collapsing glomerulopathy (Figure 4 ). There has been recent evidence suggesting that the signs and symptoms of severe COVID-19 resemble more the pathophysiology and phenotype of complement-mediated TMA (10,45,46) rather than sepsis-induced coagulopathy or DIC. In the study by Akilesh et al a total of 6 patients with evidence of kidney related TMA were described.

Two patients had a history of prior gemcitabine exposure (one of whom was an active cocaine user) while another patient was noted to have low C3 level suggestive of activation of alternative complement pathway (12) . Four patients also had evidence of collapsing glomerulopathy in addition to the TMA. Overall acute TMA and more subtle ultrastructural evidence of acute endothelial cell injury was present in 35% of the cases. Jhaveri et al described a patient with diffuse cortical necrosis and widespread glomerular microthrombi, related to defects in alternate complement pathways. (45) Another case of TMA was demonstrated on the kidney biopsy in a patient with recent Gemcitabine exposure (10) (47) . Of the patients with isolated TMA (three patients), 2 of them died and all 3 required dialysis (10, 45) . Endothelial dysfunction has been suggested as one of the main mechanisms of COVID 19 associated organ damage including acute kidney injury (13, 45, 48) The authors also postulate that COVID 19 can predispose patients to conditions that make them prone to endothelial injury like hypertension, prothrombotic states and antibody mediated rejection (12) Table 2) 

Several cases were reported where the kidney biopsy showed mixed lesions ( Table 3 ) that are consistent with TMA along with CG and ATI. Several had other findings such as diabetic nephropathy and FSGS along with post infectious glomerulonephritis in one as well. Of the 9 patients described in the literature with combined lesions that include, 5 of them are on dialysis and all are alive at the time of this writing (12) . (Table 1 and 3) 

Acute interstitial nephritis (AIN) as a secondary finding in association with collapsing glomerulopathy, FSGS and ATI has been reported in COVID 19 as well (12) . Other than that, AIN has not been reported with COVID-19.

Certain treatment-related causes of AKI in patients with COVID-19 such as the use of antiviral agents leading to tubulointerstitial diseases, (58, 59) and two cases of biopsy-proven vitamin C related oxalate nephropathy (60) have also been reported. In addition, kidney infarction has been postulated as a cause of AKI.(9,55) As suggested earlier, some authors have postulated that the TMA seen with COVID-19 could have been treatment related (50, 51) .

AKI in the kidney transplant patient with COVID 19 has been described in 8 patients in the literature ( Table 4) , two of whom were biopsied for AKI(9) One patient had Grade 2A cellular rejection and the other had ATI. The third patient who underwent a nephrectomy was found to have cortical infarction with severe interstitial fibrosis and tubular atrophy. CG has been described in an allograft recipient presenting with nephrotic syndrome and AKI whose donor was found to have low risk G0/G2 phenotype. (61) Yamda et al reported a patient with nephrotic syndrome, who had minimal change disease on the kidney biopsy whose donor was found to be positive for high risk APOL1 genotype G1/G1 (62) . In additon, studies have shown that CG can be present in TMA in the kidney allograft, possibly secondary to glomerular ischemia (49) . These pathologic findings represent the complex interplay of hemodynamic factors, cytokine storm, endothelial injury and development of DSA, all of which contribute to AKI in kidney transplant recipients. Similar to native kidneys, viral infections can precipitate collapsing glomerulopathy in transplant recipients, even with low risk APOL1 status of the donor.

In summary, SARS-Cov-2 infected patients with AKI can present with diverse pathological findings. Although direct viral infection of the kidney is possible, it is not a common or widespread finding at the time of this writing. Acute tubular injury is the most common clinical and pathologic finding in patients with AKI, both in biopsy and autopsy tissue. Collapsing glomerulopathy is the most common glomerular disease often in association with high risk APOL1 genotypes. The varied pathologic findings in the glomeruli may be a result of a heightened immune response in COVID-19 or maybe coincidental. TMA is the third most common pathology noted. Of the three pathologies described, TMA has the worst prognosis with all patients requiring dialysis. As our experience with COVID-19 grows, the kidney pathology findings will be better elucidated.

KDJ is a consultant for Astex and Natera and is a paid contributor to Uptodate.com and gets honorarium from International Society of Nephrology and the American Society of Nephrology. VB gets honorarium from International Society of Nephrology 

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