key: cord-0787615-pzlkvyjk
authors: Vijayan, Anitha; Humphreys, Benjamin D.
title: SARS-CoV-2 in the kidney: bystander or culprit?
date: 2020-09-14
journal: Nat Rev Nephrol
DOI: 10.1038/s41581-020-00354-7
sha: a99927909867bf30530558770197e81e8efe398c
doc_id: 787615
cord_uid: pzlkvyjk

A new study examined post-mortem kidney tissue from 63 patients with COVID-19. The results suggest that SARS-CoV-2 has kidney tropism, including the ability to replicate in kidney cells, and that kidney transduction by SARS-CoV-2 is associated with shorter survival time and increased incidence of acute kidney injury.

Severe acute respiratory syndrome corona virus 2 (SARS CoV2) emerged in late 2019 as a new virus causing severe respiratory illness and the COVID19 syndrome. As the outbreak evolved into a worldwide pandemic, it became evident that infection with SARS CoV2 results in multi organ disease, with a high incidence of acute kidney injury (AKI). Early reports from China did not describe the incidence and aetiology of AKI in COVID19. However, subsequent studies from China, the USA and the UK report an incidence of AKI ranging from 17% to 43% in hospitalized patients. In critically ill patients, the incidence of AKI is remarkably higher, ranging from 61% to 76% 1 . Now, Braun et al. report an association between SARS CoV2 infection of kidney cells and clinical outcomes in patients with COVID19 (ref. 2 ).

The exact pathophysiology of AKI in COVID19 has not been clearly elucidated and is probably multifactorial ( fig. 1 ). As SARSCoV2 infection can lead to a severe systemic inflammatory response and micro vascular thrombosis, AKI could be a result of haemo dynamic fluctuations leading to ischaemic tubular injury. In one series from New Orleans, USA, AKI was attributed to ischaemic acute tubular injury in 66% of series, the manifestation of collapsing FSGS in COVID19 is reminiscent of podocyto pathies associated with other viruses such as HIV, parvovirus B19 (Parvo19), BK virus and cytomegalovirus (CMV), where direct viral involvement has been documented.

The earliest evidence suggesting direct viral transduction of the kidneys in COVID19 came from a study that identified virus like inclusions in tubular cells on electron micro scopy in autopsy specimens 7 . Initially, this finding could not be replicated 6 and puta tive SARS CoV2 particles seen by electron microscopy have been alternatively interpreted as clathrin coated vesicles, micro vesicular bodies or extruded microvesicles by other researchers 8 . In the first study to confirm the kidney tropism of SARS CoV2, investigators demonstrated viral RNA by in situ hybridiza tion and PCR in all kidney compartments of autopsy specimens, most highly in glomeruli 9 . However, this study did not directly correlate the presence of viral RNA in the kidney with clinical characteristics.

The recent study by Braun et al. is the first to correlate SARS CoV2 kidney tropism with clinical outcomes 2 . The researchers collected post mortem kidney tissue from 63 patients who had COVID19 respiratory infection. It must be noted that to date, this cohort is the largest autopsy series to inves tigate SARS CoV2 and kidney tropism by a wide margin. Sixty per cent of the kidney sam ples contained SARS CoV2 mRNA. Patients whose kidney samples were SARS CoV2 positive were older, had more comorbidities and died sooner after SARS CoV2 diagnosis than patients with undetectable viral mRNA in their kidney. The presence or absence of AKI could be ascertained based on clini cal data in 39 patients. Among those who developed AKI (n = 32), kidney SARS CoV2 mRNA could be detected in 72% (n = 23), whereas in those without AKI (n = 7) viral mRNA could only be detected in 43% (n = 3).

The presence of SARS CoV2 mRNA in post mortem kidney specimens suggests that the virus can transduce kidney paren chyma, but does not provide direct evidence for such transduction. To address this impor tant issue, the researchers homogenized kid ney specimens to release SARS CoV2 viral particles and then incubated the homoge nate with cultured primate kidney tubular epithelial cells. After 2 days of incubation, cases 3 . The same researchers also reported that urine microscopy showed evidence of granular casts, which are characteristic of tubular injury, in 80% of patients. In addi tion, the onset of AKI in COVID19 has been shown to closely correlate with timing of intu bation, which is consistent with our own clini cal experience (A.V. and B.D.H., unpublished work), suggesting that haemodynamic insta bility associated with mechanical ventilation could trigger ischaemic AKI 4 .

Although ischaemic and toxic acute tubular injury undoubtedly have a role in the aetiology of COVID19associated AKI, the very high incidence of AKI in this disease prompted speculation that direct SARS CoV2 transduction of tubular epi thelial cells and perhaps podocytes contri butes to kidney injury. This hypothesis was fuelled by the fact that angiotensin converting enzyme 2 (ACE2), to which SARS CoV2 binds and which acts as the primary means of entry of the virus into the lung parenchyma, is highly expressed in the proximal kidney tubules 5 . Additional evidence suggesting possible kidney tropism of SARS CoV2 included multiple reports of collapsing focal segmental glomerulosclerosis (FSGS) in patients with COVID19. In one series of six patients with COVID19 (confirmed by positive PCR tests for SARS CoV2 from nasopharyngeal swabs), AKI and proteinuria who underwent kidney biopsy, kidney histo logy showed collapsing glomerulopathy and tubular injury 6 . Even though viral particles were not seen in the kidney tissue in this AC U T E K I D N E Y I N J U RY SARS-CoV-2 in the kidney: bystander or culprit?

A new study examined post-mortem kidney tissue from 63 patients with COVID-19. The results suggest that SARS-CoV-2 has kidney tropism, including the ability to replicate in kidney cells, and that kidney transduction by SARS-CoV-2 is associated with shorter survival time and increased incidence of acute kidney injury. SARS-CoV-2 results in multi-organ disease, with a high incidence of acute kidney injury NewS & VIewS they could detect intracellular SARS CoV2 protein and a 1,000 fold increase in viral mRNA. This experiment provides definitive evidence that kidney tissue in patients with COVID19 contains infective SARS CoV2 virus. Combined with the in situ and PCR data detecting SARS CoV2 in various kidney histological compartments, the strong impli cation is that SARS CoV2 can replicate in human kidney. However, formal proof of viral replication in human kidney cells remains to be shown.

This study represents an important step forwards in the rapidly growing body of evi dence concerning SARS CoV2, kidney tro pism and clinical outcomes. The recovery of viable SARS CoV2 from kidney provides the strongest evidence yet that the kidney is a tar get of the virus. One implication of this find ing is that urine testing for viral mRNA might help to risk stratify patients with COVID19. The observation that SARS CoV2 kidney tropism is associated with premature death is consistent with the hypothesis that the virus might directly drive kidney injury. Chronic kidney disease has recently been identified

Systemic inflammation and microvascular thrombosis

Haemodynamic instability Viral transduction of kidney cells Ischaemic tubular injury Acute kidney injury Collapsing glomerulopathy and tubular injury as the strongest risk factor for COVID19 related death -stronger even that chronic heart or lung disease -and one can speculate that this finding may also reflect SARS CoV2 kidney tropism 10 .

In summary, the study by Braun et al. provides important information regard ing the kidney tropism of SARS CoV2 in COVID19 and associates this tropism with disease seve rity. Future studies like this one are needed to better understand the cause of AKI in COVID19 and to ultimately design effective therapeutic and kidney protective strategies.

Acute kidney injury

SARS-CoV-2 renal tropism associates with acute kidney injury

Acute kidney Iinjury associated with coronavirus disease 2019 in urban New Orleans

Acute kidney injury in patients hospitalized with COVID-19

Acute kidney injury in COVID-19: emerging evidence of a distinct pathophysiology

AKI and collapsing glomerulopathy associated with COVID-19 and APOL 1 high-risk genotype

Ultrastructural evidence for direct renal infection with SARS-CoV-2

Electron microscopic investigations in COVID-19: not all crowns are coronas

Multiorgan and renal tropism of SARS-CoV-2

Factors associated with COVID-19-related death using OpenSAFELY

The authors declare no competing interests. kidney tissue in patients with COVID-19 contains infective SARS-CoV-2 virus