Since the outbreak of COVID-19 disease, a bidirectional interaction between kidney disease and the progression of COVID-19 has been demonstrated. Kidney disease is an independent risk factor for mortality of patients with COVID-19 as well as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection leading to the development of acute kidney injury (AKI) and chronic kidney disease (CKD) in patients with COVID-19. However, the detection of kidney damage in patients with COVID-19 may not occur until an advanced stage based on the current clinical blood and urinary examinations. Some studies have pointed out the development of subclinical acute kidney injury (subAKI) syndrome with COVID-19. This syndrome is characterized by significant tubule interstitial injury without changes in the estimated glomerular filtration rate. Despite the complexity of the mechanism(s) underlying the development of subAKI, the involvement of changes in the protein endocytosis machinery in proximal tubule (PT) epithelial cells (PTECs) has been proposed.
COVID-19, a syndrome caused by severe acute respiratory syndrome (SARS) coronavirus 2 (SARS-CoV-2), has had a major impact on humanity on a global scale since December 2019 
. Initially described as causing SARS associated with high mortality and morbidity, it is now accepted that COVID-19 promotes multiple organ dysfunction 
. Unprecedented scientific effort has advanced people's understanding of the disease pathogenesis and progression, leading to significant improvements in the clinical management of COVID-19 such as treatment with antivirals and monoclonal antibodies, and the development of standardized protocols for the treatment of hospitalized patients as well as vaccination campaigns 
. Despite these advances, knowledge regarding the pathogenesis of multiple organ dysfunction in COVID-19 is still poorly known.
The kidney is a key target of SARS-CoV-2 
. Several reports indicate a high prevalence of acute kidney injury (AKI) in patients with severe COVID-19 
. Conversely, AKI and chronic kidney disease (CKD) are independent risk factors associated with COVID-19 severity and mortality 
. According to the Kidney Disease Improving Global Outcomes (KDIGO) guidelines, AKI is characterized by an increase in the serum creatinine level >0.3 mg/dL within 48 h, a 1.5-fold increase in serum creatinine level compared with baseline within 7 days, and/or urine output <0.5 mL/kg/h for 6 h 
. An important pitfall, however, is the threshold of serum creatinine sensitivity, which increases in response to a decline in the estimated glomerular filtration rate (eGFR) >50% due to renal functional reserve 
. This process delays the identification of kidney injury, which could be associated with a worse outcome in patients with COVID-19.
The use of biomarkers of tubular injury to determine early kidney damage created a new concept called subclinical AKI (subAKI) 
. So far, there is no consensus regarding a specific definition of subAKI. Based on recent reports, the researchers propose that subAKI represents a large spectrum of parenchymal kidney damage without changes in glomerular function, defined by the KDIGO criteria, associated with the presence of biomarkers of kidney damage in urine 
. Tubular injury biomarkers in urine can include β2-microglobulin and kidney injury molecule 1 (KIM-1), markers of proximal injury, and neutrophil gelatinase-associated lipocalin (NGAL), a marker of distal injury 
. The presence of these biomarkers in the urine is usually associated with microalbuminuria 
. At present, subAKI is recognized as an emerging syndrome and a risk factor for the development of AKI and CKD 
. In addition, subAKI predicts adverse outcomes such as the requirement for dialysis and mortality in patients without established AKI 
. Therefore, precocious identification of subAKI could improve the treatment and outcome of patients with kidney injury. However, clinical data regarding the development of subAKI and its involvement with COVID-19 prognosis are still poorly known.
2. COVID-19 and Kidney Disease
Data from the Acute Disease Quality Initiative Workgroup indicate that approximately 20% of patients hospitalized with COVID-19 develop AKI, and the prevalence increases to approximately 50% in patients admitted to intensive care units 
. A systematic review comprising 30,639 patients hospitalized with COVID-19 reported similar results 
. Further, it was observed that the use of kidney replacement therapy ranged from 9% in hospitalized patients to 20% in patients in an intensive care unit.
Conversely, renal dysfunction is an independent risk factor for poor prognosis of patients with COVID-19 
. A study using the OpenSAFELY platform with records from approximately 17 million patients showed that reduced renal function, measured by eGFR, is a key risk factor for COVID-associated mortality 
. Dialysis or kidney failure increases the risk of mortality due to COVID-19 by 3.7-fold. Patients with COVID-19 who develop AKI have a lower eGFR than patients with COVID-19-independent AKI. These observations corroborate the idea that patients with COVID-19 develop more severe kidney injury 
An increasing number of reports suggest that patients who have had acute COVID-19 might experience persistent renal dysfunction after discharge 
. Yende and Parikh 
proposed that subclinical inflammation and injury may persist for many months after the diagnosis of COVID-19, which increases the risk of the development of AKI and CKD. In accordance, Al-Aly et al. 
, in a cohort study (with 6 months follow-up) using the US Department of Veterans Health Affairs database, observed that patients with COVID-19 presented a higher risk of kidney injury even after the first 30 days since diagnosis. In another cohort study on 89,216 patients, it was shown that COVID-19 survivors have an increased risk of developing AKI, a decline in eGFR, progression to ESRD and major kidney disease events 
. Despite the evidence suggesting that a decline in renal function might be a symptom post-COVID, future clinical studies should verify if persistent renal injury after acute COVID-19 is caused by SARS-CoV-2 infection and/or a result of healthcare restrictions during the pandemic 
In a 6-month follow-up study, Huang et al. 
showed that 13% of patients with COVID-19 without clinical AKI presented a decline in eGFR. This observation indicates the development of a silent kidney injury, such as subAKI, during acute COVID-19. In a retrospective cohort study, markers of subAKI, such as proteinuria and urinary β2-microglobulin, were associated with the severity of COVID-19 and a lower rate of hospital discharge, despite unchanged eGFR 
. In a recent review, Legrand et al. 
pointed out the possible role of subAKI in patients with COVID-19. They commented that a late diagnosis, based on the KDIGO guidelines, could contribute to a poor prognosis in patients with COVID-19. Although the development of AKI is usually associated with severe COVID-19, it has been shown that subAKI develops in patients with mild to moderate COVID-19, including children 
. These observations emphasize the importance of the timely identification of subAKI in patients with COVID-19. In a prospective study, the presence of urinary biomarkers was associated with adverse kidney outcomes in patients hospitalized with COVID-19 
3. Proximal Tubule Epithelial Cells Are a Target for the Development of subAKI in Patients with COVID-19
The hallmark of subAKI is PT injury associated with a pro-inflammatory and pro-fibrotic phenotype leading to tubule interstitial injury 
. Interestingly, PTECs have been proposed to be a primary site of SARS-CoV-2 replication in the kidney 
. Rahmani et al. 
, using scRNA sequencing, showed that PTECs have high potential co-expression of SARS-CoV-2 receptors and proteases involved in cell infection, such as ACE2, NPR-1, TMPRSS2, CTSB, and FURIN.
Alternative routes for SARS-CoV-2 cell infection have also been proposed. Wang et al. 
showed that CD147 mediates the entry of SARS-CoV-2 in VeroE6 cells (monkey renal cells) and BEAS-2B cells (human bronchiolar cells). The authors revealed that human CD147 (also known as Basigin) allows entry of the virus into non-susceptible BHK-21 cells (hamster renal fibroblast cells). CD147 is highly expressed in the basolateral side of PTECs 
. Mori et al. 
showed that LLC-PK1 cells (porcine PTEC line) expressed human KIM-1, which supported the uptake of pseudovirus displaying the SARS-CoV-2 spike protein. Interestingly, KIM-1 is increased in PTECs during the development of subAKI and AKI 
Based on these observations, it is plausible to postulate that the direct infection of PT epithelial cells (PTECs) with SARS-CoV-2 could be a central mechanism for the development of subAKI in patients with COVID-19. In agreement, Caceres et al. 
showed that there is a correlation between the presence of SARS-CoV-2 in the urine and the incidence of AKI and mortality in patients with COVID-19. However, so far, there are no studies showing a direct correlation between SARS-CoV-2 infection in renal cells and the development of AKI in patients with COVID-19. Multiple organ damage could also be involved in the deleterious effect of SARS-CoV-2 on kidney function as seen with hemodynamic changes and/or an exacerbated immune response, such as cytokine storm 
. PTECs express different cytokine receptors, including IL-6R 
, IL-4R 
, and TNF-αR 
. There is an association between plasma levels of IL-6 and the development of AKI in patients with COVID-19 
. Medeiros et al. 
showed that AKI associated with COVID-19 is accompanied by significant alterations in circulating levels of immune mediators such as IFN-γ, IL-2, IL-6, TNF-α, IL-1Ra, IL-10, and VEGF. They postulated that this phenomenon could contribute to the establishment of AKI. In another study, using urine collected from 29 patients with COVID-19 admitted to the intensive care unit, strong correlations between pro-inflammatory cytokines and AKI were observed 
Saygili et al. 
showed an association between the neutrophil count and the development of AKI, pointing out the role of inflammation in this process. This hypothesis is reinforced by the observation, in a comparative study, that the prevalence of AKI in patients with COVID-19 is similar to that in patients infected with seasonal influenza 
. Despite the similar prevalence, COVID-19 was associated with a higher risk of developing stage 3 AKI and higher proteinuria rates than influenza infection, suggesting that additional mechanisms participate in the renal injury associated with COVID-19.