Kidney Injury in COVID-19 Patients, Drug Development And Their Renal Complications: Review Study

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A B S T R A C T

Since December 2019, the world was encountered a new disease called coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although SARS-CoV-2 initially causes lung damage, it also affects many other organs, including the kidneys, and on average, 5–23% of people with COVID-19 develop the symptoms of acute kidney injury (AKI), including elevated blood creatinine and urea, hematuria, proteinuria, and histopathological damages. The exact mechanism is unknown, but the researchers believe that SARS-CoV-2, directly and indirectly, affects the kidneys. The direct pathway is by binding the virus to ACE2 receptor in the kidney, damage to cells, the renin-angiotensin system disturbances, activating coagulation pathways, and damaging the renal vascular endothelium. The initial evidence from studying the kidney tissue in postmortem patients is more in favor of the direct pathway. The indirect pathway is created by increased cytokines and cytokine storm, sepsis, circulatory disturbances, hypoxemia, as well as using nephrotoxic drugs. Using renal tissue biopsy and autopsy in patients with COVID-19, recent studies found evidence for a pre-dominant indirect pathway in AKI induction by SARS-CoV-2. Besides, some studies showed that the degree of acute tubular injury (ATI) in autopsies from COVID-19 victims is milder compared to AKI degree. We review the mechanism of AKI induction and the renal side effects of the most common drugs used to treat COVID-19 after the overview of the latest findings on SARS-CoV-2 pathogenicity.

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1. Introduction

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a virus of coronaviridae family which has single-stranded RNA and causes coronavirus disease-2019 (COVID-19) [1]. Seven coronaviruses were identified that cause the disease in humans [2,3]; four of them are endemic worldwide and cause a mild seasonal respiratory illness. These four viruses infect the upper respiratory tract and are low pathogenic coronaviruses. Highly pathogenic coronaviruses infect the lower respiratory tract and include severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MER- S-CoV), and severe acute respiratory syndrome coronavirus 2 (SAR- S-CoV-2). SARS-CoV caused an epidemic in humans in 2002 for one year which had a fatality rate of about 10% [4]. MERS-CoV caused an epidemic in humans in 2012. Although MERS-CoV incidence was lower than that of SARS-CoV, the case fatality ratio (CFR) was reported to be higher at about 35% [2]. The new member of this family is SARS-CoV-2 which caused an epidemic in late 2019, and the resulting disease was named coronavirus disease-2019 (COVID-19). The disease rapidly spread worldwide and became a global problem, being recognized as a pandemic disease by World Health Organization (WHO) on March 11, 2020 [5]. At the time of writing this review (June 2021), the virus has infected more than 180 million people in 223 countries, killed more than 4000,000, and more than 3 billion vaccine doses were administered [6]. Preliminary reports indicate that about 81% of people infected with SARS-CoV-2 have only mild symptoms, and only 5% show severe symptoms. The mortality rate in COVID-19 is reported to be about 2–4% [2]. The disease initially damages the lungs but also affects many other organs including the kidneys, and causes renal malfunction [7]. Hence, up to 25% of people with severe COVID-19 develop acute kidney injury (AKI) symptoms [8]. After the overview of the latest findings on COVID-19 pathophysiology, we focus on SARS-CoV-2 induced renal impairment etiology and the most commonly used drugs for COVID-19 treatment, along with renal side effects of these drugs. Then, the most important new variants are mentioned.

* Corresponding author at Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran.

E-mail address: hnajafi@kums.ac.ir (H. Najafi).

https://doi.org/10.1016/j.biopha.2021.111966

Received 18 May 2021; Received in revised form 15 July 2021; Accepted 23 July 2021

Available online on 27 July 2021

0753-3322/© 2021 The Authors. Published by Elsevier Masson SAS. This is an open-access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Z. Mohamadi Yarijani and H. Najafi

2. Pathogenesis of COVID-19

SARS-CoV-2 genome encodes structural and non-structural proteins. Structural proteins include spike (S), membrane (M), nucleocapsid (N), and envelope (E) proteins. Several nonstructural proteins play a key role in virus entering and replication in the host cells [9]. The first step in SARS-CoV-2 pathogenesis is the binding of S protein to the angiotensin-converting enzyme-2 (ACE2) receptor [10]. The binding affinity of S protein to ACE2 in SARS-CoV-2 is 10–20 times higher than that of SARS-CoV [11]. Moreover, transmembrane serine protease 2 (TMPRSS2) is required for coronavirus to enter host cells [3]. Spike protein was shown to bind to ACE2 on alveolar epithelial type II cells using TMPRSS2, and the virus enters the cell via endocytosis (Fig. 1). Then, the virus releases its RNA into the host cell, and after translation, the viral proteins are produced in the endoplasmic reticulum and Golgi apparatus. Furthermore, viral RNA replicates using the cell’s transcription machine. Finally, after the synthesis of structural and non-structural proteins, viral RNA and synthesized proteins are assembled and a new virus is released from the cell by exocytosis [12–14].

Following the replication and enhancement of SARS-CoV-2, the molecular patterns of the virus (including proteins, nucleic acids, and pathogen components) are detected by the innate immune system components including pattern recognition receptors. These receptors then stimulate the expression of inflammatory mediators which lead to cytokine storms through activating NF-κB and MAPK [3,15]. It was shown that the cytokine storm is associated with disease severity [14]. Moreover, SARS-CoV-2 was shown to increase blood coagulation factors and blood clotting ability in patients [16]. The main mediators of

Fig. 1. Schematic representation of SARS-CoV-2 binding to host cells and using host machinery for replication. ERGIC: Endoplasmic reticulum-Golgi intermediate compartment.

blood clotting (including fibrinogen, tissue factor, and thrombin) act as proinflammatory factors. SARS-CoV-2 increases fibrinogen expression and fibrinogen cause platelet aggregation and immune system activation [17]. On the other hand, hypoxia due to COVID-19 also accelerates thrombosis formation by increasing blood viscosity [18]. Finally, vascular endothelial function is impaired by COVID-19 infection, which in turn increases thrombin production and inhibits fibrinolysin, thereby increasing blood clotting ability [16]. Therefore, clot formation in the blood vessels of people with COVID-19 is a risk factor that increases the mortality rate and causes anticoagulants to be prescribed in these patients [19].

3. Epidemiology and pathophysiology of COVID-19 induced acute kidney injury

Although coronavirus primarily appears as an acute respiratory disease, it can affect other organs, including the kidneys, heart, gastrointestinal tract, blood, and central nervous system [20,21]. Coronavirus penetrates the central nervous system through nerve cells, and it causes damage to the respiratory center, confusion, lethargy, disorientation, loss of sense of smell and taste in most patients, and other symptoms related to brain dysfunction [22]. Coronavirus in the kidney can cause AKI and other disturbances in kidney function [23,24]. Acute kidney injury is a condition in which blood urea and creatinine concentrations increase via the retention of nitrogenous wastes, decrease GFR, as well as extracellular fluid volume and electrolyte homeostasis derangement [25–27]. Although AKI is an uncommon feature of SARS-CoV-2, it is known to be a fatal complication with early reports indicating a 3–9% prevalence of AKI in patients with COVID-19 [28]. However, subsequent studies reported that AKI incidence in hospitalized patients with COVID-19 is from 5% to 23% [8,29–31], and recent cohort studies have even reported an incidence of up to 46% which has reached 68% in ICU patients [32,33]. Risk factors for AKI in COVID-19 include the need for mechanical ventilation, intubation, old age, diabetes mellitus, hypertension, severe illness, obesity, male gender, and chronic renal failure [33,34]. However, some studies showed that patients with COVID-19, in addition to AKI, also develop glomerular disease because hematuria and proteinuria have also been detected in them [31].

The exact COVID-19 mechanism in the kidney is not yet known, but researchers believe that SARS-CoV-2, directly and indirectly, affects the kidney. Because SARS-CoV-2 is found in the urine, the kidney damage pattern caused by the virus is limited to areas with ACE2 receptors, and the time course in which the virus appears in the urine coincides with the onset of AKI, so it was suggested that the virus directly affects the kidneys [35–37]. The virus is claimed to enter the kidney cell by binding to membrane-bound ACE2 receptors in the glomerular podocyte cells and the apical membrane of proximal tubule cells, and in addition to damaging the kidney epithelial cells, it disarranges the balance of renin-angiotensin system [38]. The angiotensinogen is primarily converted to angiotensin-I by renin and then to angiotensin-II under the influence of the angiotensin-converting enzyme (ACE). Moreover, angiotensin-II is converted to angiotensin 1–7 by the ACE2 which dilates blood vessels. If SARS-CoV-2 occupies ACE2, angiotensin-II levels increase, leading to vasoconstriction, glomerular dysfunction, inflammation, and fibrosis [38,39]. Recently Wang et al. and Chiu et al. found that SARS-CoV-2 also invades host cells via the CD 147-spike protein pathway and this glycoprotein is highly expressed in the proximal tubule [40,41]. Moreover, SARS-CoV-2 causes kidney damage by activating inflammatory pathways and cytokine storm, activating coagulation pathways, damage to renal vascular endothelium, sepsis, hemodynamic instability as well as hypoxemia [38,42,43]. Viral infection of the endothelium via immune cell recruitment causes defective endothelial function and re- duces the production of vasodilators, including nitric oxide. Decreased vasodilators increase the response to vasoconstrictors and, together with ischemia-induced oxidative stress lead to AKI

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Biomedicine & Pharmacotherapy 142 (2021) 111966

development [44].

Furthermore, there are different opinions about the timing of the onset of AKI symptoms in different studies. In a study conducted by Na et al. out of 66 patients with COVID-19, three cases showed AKI symptoms, all of which became apparent in the severe patients after the first week of hospitalization [20]. Other studies have also reported the onset of AKI symptoms from days 5–9 after the hospitalization [24,45,46]. However, in one case report, symptoms started on the second day of hospitalization [47], and in four other studies, there were symptoms at the time of admission [48–51].

4. Pathological findings in COVID-19-induced acute kidney injury

Preliminary pathological findings regarding renal injury in people with COVID-19 are mainly the result of studies performed on post-mortem tissues (Autopsy). Due to a study by Su et al. on autopsy specimens using a light microscope, renal damages included acute tubular damage in the proximal tubule, brush border loss, lumen dilation, vacuolar degeneration, and sometimes necrosis, and tubular epithelial detachment [52]. The tubular casts, sometimes cell swelling and interstitial edema without inflammation in the distal tubule and collecting ducts, accumulation of erythrocytes, obstruction of glomerular and peritubular capillaries, segmental thrombus in glomerular capillaries with glomerular ischemia along with endothelial damage and swelling were observed. In the electron microscopic study, virus particles were observed in the cytoplasm of proximal tubule cells and podocytes which this evidence is in favor of the fact that SARS-CoV-2 directly causes kidney damage. Furthermore, indirect fluorescence expressed the SARS-CoV-2-related nucleoprotein in the tubular epithelium. Other studies have also reported evidence of the SARS-CoV-2 virus in the autopsy specimens of COVID-19 patients [53,54].

The second category of findings comes from the research on the tissues obtained from kidney biopsy and autopsy in COVID-19 patients. These findings include immune-mediated glomerular disease and glomerulosclerosis, and no viral particles were found in the cytoplasm of cells [55]. In a recent study by Kudos et al. on 17 patients with COVID-19, they reported that collapsing glomerulopathy with acute tubular injury (ATI), tubuloreticular inclusions, minimal change disease, endothelial damage, pigment casts, and immune-mediated glomerular disease were observed in biopsy specimens using a light microscope [56]. Electron microscopy also showed glomerular endothelial tubuloreticular inclusion and the absence of viral particles in kidney cells. Immunohistochemical staining and automatic in situ hybridization indicated the absence of spike and nucleocapsid proteins and RNA of SARS-CoV-2 virus in renal cells. However, in manual in situ hybridization, the presence of RNA in tubular cells was slightly positive in two patients.

In line with the above-mentioned results, it was shown that SARS-CoV-2 RNA is not found in the urine of all patients with COVID-19 induced AKI according to plasma creatinine concentration [57]. This finding indicates that urinary secretion of the virus is not common in patients with AKI following COVID-19. Therefore, the virus does not directly cause kidney damage, because in this case, the virus was secreted into the urine. Furthermore, Tampa et al. showed that urinary levels of SARS-CoV-2 nucleocapsid protein in the patients were directly related to the risk of AKI, but urinary ACE2 and TMPRSS2 protein levels were not associated with AKI [58]. The researchers concluded that since urinary levels of ACE2 and TMPRSS2 proteins are not associated with AKI, SARS-CoV-2 affects the kidneys via systemic inflammation rather than directly.

Besides, Santoriello et al. examined the kidneys of 42 patients who had died of COVID-19 [59]. They studied all autopsies with light microscopy, electron microscopy, immunofluorescence, and in situ hybridization. This study’s results showed that the ATI degree in these autopsies is milder compared to the AKI degree. They suggested that several

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Z. Mohamadi Yarijani and H. Najafi

factors, including ischemia, hypoxia, toxins, and other factors, may play a role in the development of AKI following COVID-19.

Therefore, it seems that the findings of some studies on postmortem tissues further confirm the direct damage to the kidney by SARS-CoV-2. However, in the studies with biopsy specimens, the presence of virus in kidney cells is negligible, and it is suspected that such a small amount of virus is sufficient to cause pathological changes and agrees with the predominant role of cytokines and other systemic effects.

5. Drugs used to treat COVID-19 and their renal complications

There are several potential approaches for COVOD-19 treatment including drugs, monoclonal antibodies, peptides, interferon, and so on; hence, we review drugs that have side effects on the kidneys (Table 1).

5.1. Lopinavir/ritonavir

Lopinavir/ritonavir (KALETRA) was approved for HIV patients, and its mechanism of action is protease inhibition. In humans, lopinavir is used with ritonavir because ritonavir increases the plasma half-life of lopinavir by inhibiting cytochrome P450 [60]. In a study, Alvarez et al. estimated that a 50% effective concentration of lopinavir against the SARS-CoV-2 virus is 16.7 mg/L. Their model indicated that with a dose of 400 mg (b.i.d) about 40% of patients remain below the minimum effective concentration. But with 1200 mg, this proportion reduces to 22% [61].

Lopinavir was shown to have inhibitory activity in vitro against SARS-CoV, SARS-CoV-2, and MERS-CoV [62–65]. Although COVID-19 treatment with lopinavir/ritonavir was recommended in many studies, the results of one study showed that lopinavir/ritonavir could not be an effective treatment for hospitalized patients with COVID-19 [66]. This study’s results showed that using the lopinavir/ritonavir for the treatment of 199 patients with COVID-19 did not significantly reduce mortality and ICU admission.

In a study using World Health Organization Drug Base (VigiBase) performed by Binois et al., all patients with COVID-19 who were taking lopinavir/ritonavir and had acute kidney injuries were extracted from the database. They showed that there were 8 COVID-19 patients who developed type 2 or 3 acute kidney injury on the second or third day of hospitalization in the ICU after receiving lopinavir/ritonavir [67]. Due to these studies, lopinavir/ritonavir may also have synergistic effects with COVID-19 in developing acute kidney injury which requires further study.

5.2. Vancomycin

Vancomycin is an antibiotic used to treat pneumonia against gram-positive bacteria, especially Staphylococcus aureus [68]. This drug penetrates into most spaces of the body, and its concentration depends on the degree of inflammation [69]. In some studies, vancomycin has also been used to treat pneumonia caused by COVID-9 [20,70]. A 33-year-old pregnant woman with COVID-19 increased her blood urea and creatinine after taking vancomycin in a case report. In this patient, the vancomycin was discontinued due to renal function deterioration after a few days, and creatinine and urea were severely reduced on the sixth day after hemodialysis [45]. In another study of 3 patients with acute kidney injury following COVID-19, blood creatinine and urea concentrations increased after starting vancomycin, indicating acute kidney injury, and discontinuation of vancomycin caused a return of blood creatinine and urea concentrations in some of them [20]. Furthermore, it is difficult to determine whether acute kidney injury was caused by SARS-CoV-2 infection alone or treatment with vancomycin has also helped. Since in both studies, acute kidney injury started after using vancomycin, the possibility of nephrotoxicity of this drug and its synergistic effects with the adverse effects of SARS-CoV-2 on the kidney is raised.

5.3. Remdesivir

Remdesivir is a modern nucleotide analog that is effective against coronaviruses such as SARS-CoV and MERS-CoV in vitro and in animal studies, as well as in SARS-CoV-2 in vitro [71,72]. It was reported that remdesivir inhibits RNA synthesis in SARS-CoV, MERS CoV, and SARS-CoV-2 [73]. Although US Food and Drug Administration (FDA) has not approved any definitive drug to treat COVID-19, it has authorized the emergency use of remdesivir to treat hospitalized adults [74]. Humeniuk et al. in their study found that single-dose i.v. admin- istration of remdesivir as a solution or lyophilized formulation at doses ranging from 3 to 225 mg and multiple-dose i.v. administration of 150 mg once daily for 7 or 14 days is generally well-tolerated. No subject had a graded ALT or AST elevation in a single-dose study, but mild elevations in ALT and AST were observed in the multiple-dose study [75]. Recent studies showed that remdesivir prevents SARS-CoV-2 infection by inhibiting virus replication in human respiratory tract epithelial cells which is, therefore, a potential therapeutic drug against

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