Crosstalk Between COVID-19 Infection And Kidney Diseases: A Review On The Metabolomic Approaches Ⅱ

4. Metabolomics, COVID-19, and Kidney Injury 

Compared to the proteome or transcriptome, metabolomics is more accurate in measuring a cell’s metabolic state [125]. In contrast to current PCR and antibody tests, metabolomics studies will help measure and assess the effects on the host as well as the occurrence of the infecting agent. As a result, metabolomic studies may offer a set of markers that are useful for rapid tests to confirm infection by COVID-19, the disease severity, and the likelihood of a positive outcome. Metabolomics has been ongoing in various studies, especially examining COVID-19 infection in humans [126,127]. Understanding COVID-19’s impact on host metabolism is still important to better understand the variety of clinical presentations and provide better treatments for those affected. Metabolic profiling can find biomarkers unlike RT-PCR and can be utilized as a diagnostic and a prognostic approach, which is essential for predicting future epidemics, particularly in COVID-19 scenarios [128]. It has been remarkable how quickly COVID-19 has carried out its genome-wide association studies (GWAS), due in part to the collaborative networks set up during previous GWAS and the use of previously genotyped study populations such as UK Biobank and AncestryDNA [129–132]. GRASP portal Covid-19 GWAS results reveal potential SARS-CoV-2 modifiers [133]. 

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Urinary metabolites from several biochemical pathways distinguish between AKI and non-AKI in COVID-19-infected individuals hospitalized. They point to a conserved defect in NAD+ production as a possible new therapeutic target to treat AKI brought on by COVID-19 [134]. ADAM17, a disintegrin and metalloproteinase 17 is identified as the protease responsible for the shedding of ACE2, which is the cellular receptor of SARS-CoV [135]. The proteolytic action of ADAM17 also releases the soluble forms of TNF and its receptors TNFR1 and TNFR2, which are pro-inflammatory molecules [136]. Increased expression of TNFR1 and ACE2 will worsen the prognosis of COVID-19 [137]. The downregulation of ACE2 upon infection would enhance the renal levels of Ang-II and the oxidative stress induced by Ang-II, resulting in increased renal injury [138]. According to the study of Vergara et al., urine ACE2 (uACE2) is increased in COVID-19 patients. It increased far more in patients with AKI and strongly correlated with TNFR1 and uTNFR2. In kidney sections, elevated uACE2 was associated with tubular loss of ACE2. Increased excretion of amino acids such as tryptophan, leucine, isoleucine, and phenylalanine was observed in the urine metabolome study of the COVID-19 patients, which suggested a strong correlation between uACE2 and urine amino acids [139]. 

4.1. Untargeted Metabolomics in COVID-19 and Other Metabolomics Technologies

Global detection and relative quantification of small molecules in a given sample is the primary focus of untargeted metabolomics, while targeted, in contrast, focuses on quantifying specific groups of metabolites and offers the possibility of absolute quantification [140,141]. Untargeted metabolomics often compares the metabolomes of the experimental samples and control groups to find differences in the metabolite profiles of the two groups. These metabolomic variations could be significant for particular biological circumstances [142,143].

An untargeted metabolomic study was conducted by Chen et al., where they investigated the difference between the metabolites present in the serum of 20 healthy and 20 COVID-19-affected patients with the help of high-resolution UHPLC-MS/MS [144]. 714 metabolites were identified in the study, and around 203 metabolites were found to be different compared to healthy and infected samples. Another untargeted metabolomic analysis was performed using the saliva samples collected from the infected patients. There were statistically significant changes in a number of the detected metabolites between people with high and low severity [145]. Another prior research discovered that salivary 2-pyrrolidineacetic acid and Myo-inositol could discriminate between inpatient and outpatient cohorts [146]. A metabolomic analysis has been used to screen for metabolic changes and to give a thorough understanding of endogenous metabolites. The untargeted metabolomics study identified 2466 metabolite peaks totaling 631 and 1835 differential metabolites in negative and positive ion modes, respectively. Among 240 metabolites, 193 were substantially linked to COVID-19 [147].

As a result of an integrated analysis of 139 COVID-19 patients’ clinical measurements, immune cells, and plasma multi-omics, Su et al. identified a major change between mild and moderate COVID-19 disease, at which point inflammatory signaling is elevated and specific metabolites and metabolic processes are lost. A single axis of immune features was condensed from 120,000 immune features and aligned separately with changes in plasma composition, clinical measures of blood clotting, and transitions between mild and moderate disease to illustrate how different immune cell classes coordinate in response to SARSCoV-2 [148]. Single-cell metabolomics is an emerging technology in metabolomics including mass-spectrometry-based single-cell metabolomics [149,150], microfluidic-based single-cell metabolomics [151], supermolecular probe-based metabolic uptake competition assay [152], or Raman spectroscopy based single-cell or even subcellular metabolomics [153,154]. These are four different categories of methods that could be complementary to each other. A multi-omic analysis of single cells can also be done by integrating single-cell metabolic analysis with other omics, such as proteomics [148,155]. These techniques could be useful due to its potential applications in COVID-19 and kidney disease. 

4.2. Antiviral Drug Efficacy in COVID-19

Several experimental methods, such as repurposing RNA polymerase-inhibiting and tiviral medications, have improved the health outcomes for COVID-19 patients. To combat COVID-19, effective antiviral medicines are crucial. There has been evidence that lopinavir and various IFs, notably IF- β, have moderate anti-SARS-CoV efficacy in vitro [156]. It was also noted that another drug called ribavirin, showed synergistic effects against COVID- 19 [157]. It was also demonstrated that lopinavir-ritonavir or IF-β1b could lower viral load and improve lung histology [158]. Intranasal leukocytic IF-α or IF-β1a are expected to be useful for prophylaxis against SARS without a successful vaccination. The best combination appears to be IF-α, IF- β1a, and ribavirin. A combination with a brief course of ribavirin seems appropriate since IFs might not be efficient in causing an antiviral response in the uninfected host cells within the first 24 h [157]. 

A computational study analyzed commonly used drugs, including Favipiravir, Remdesivir, Nitazoxanide, Galidesivirm, and Ribavirin [159]. Monitoring the bioenergetic state of patients may aid in explaining why some patients respond well to a specific replicatranscriptase inhibitor while others do not. According to this viewpoint, medications with high ATP reliance will be less successful in treating patients with advanced metabolic dysfunction. Therefore, it is suggested that individuals with a near-normal metabolic profile might have a greater probability of responding to ribavirin or favipiravir. These medicines need multiple-stage functionalization [160]. Many drugs used to treat COVID-19 are known to cause AKI [161] (Table 1). 

Table 1. COVID-19 drugs causing kidney injury

4.3. Metabolites Involved in the Diagnosis and Prognosis of COVID-19

Several pilot experiments were carried out to determine and identify the COVID-19 connected to volatile organic compound (VOC) indicators and assess the potential for COVID-19 testing in contrast to conventional RT-qPCR. In an untargeted metabolomic study, VOCs including methylpent-2-enal, 1-chloroheptane, 2,4-octadiene and nonanal in the breath of COVID-19 patients were found to be elevated significantly [26]. The initiation of the immunological responses in COVID-19 includes several metabolic pathways, including the metabolism of amino acids, energy, and lipids. Arachidonic acid is an inherently bioactive antiviral lipid, and it has been hypothesized that this metabolic route significantly impacts COVID-19 susceptibility [169]. It was also observed that in the pathogenesis of COVID-19, cyclooxygenase-2 (COX-2) and prostaglandins, notably PGE2, have pro-inflammatory effects. Additionally, hybrid drugs, such as COX-2 inhibitors, can potentially treat patients with COVID-19 by regulating the total balance of arachidonic acid mediators [170]. 

Profiling small metabolites and macromolecules allows measuring the host’s response to the infection. A human antiviral metabolite, 30 -Deoxy-30 ,40 -didehydro-cytidine, was shown to be considerably higher in COVID-19 patients [171]. Compared to the non-COVID-19- 19 and healthy groups, the 15-HETE levels identified in the COVID-19 individuals were significantly depleted. The lack of anti-inflammatory signals brought on by the reduction of 15-HETE may be a factor in the increased inflammation observed during COVID-19 infection [172]. A targeted metabolomic study analyzed and identified AMP, dGMP, snglycerol-3-phosphocholine, and carnitine metabolites that were dysregulated in patients with COVID-19 [173]. The study by Lee et al. analyzing plasma metabolite and protein levels, as well as single-cell multi-omics analyses collected during the first week after clinical diagnosis, metabolic changes associated with peripheral immune responses in 198 COVID-19 patients were reported in a large cohort study of healthy donors. Plasma metabolites like acetoacetate, which is formed in response to poor cellular glucose uptake, and α-ketobutyrate, which is implicated in the development of an early insulin resistance biomarker, α-hydroxybutyrate, can be used to predict future outcomes of newly diagnosed COVID-19 patients. These metabolites are well-known in other disorders with COVID- 19-like pathogenesis. It may be possible to predict the survival rates by combining the measurement of these plasma metabolites with cell-type-specific metabolic reprogramming networks that are linked to disease severity [174]. More studies are required to analyze and understand different metabolites to help diagnose the infected patients faster. 

4.4. Alteration of Plasma Metabolomics in COVID-19

According to the level of immunological response, different plasma metabolic profiles were seen, indicating the importance of the metabolism of amino acids and the lipid profile acting as indicators of how well a vaccine will work. Alterations in metabolomics in the plasma were detected in different studies. In one such study, alterations in plasma were analyzed, and changes in different amino acids and lipid profiles were detected as a response to vaccination against COVID-19 [175]. COVID-19 patients’ lipid and metabolite changes correlate with their disease progression, suggesting that COVID-19 impacted their entire body metabolism. Particularly, altered energy metabolism and hepatic dysfunction are brought on by malic acid of the TCA cycle as well as the carbamoyl phosphate of the urea cycle [176]. Another metabolomic pathway analysis revealed that the individuals affected with COVID- 19 were found to have an impact on glycerophospholipid and porphyrin metabolism but at the same time showed a significant effect on the glycerophospholipid and linoleic acid metabolism pathways [177]. Shen et al., analyzed the proteome and metabolome of the sera from several COVID-19 patients by applying proteomics and metabolomics to test whether any characteristic molecular changes are induced by SARS-CoV-2. Proteomic and metabolomic studies revealed molecular changes in the sera of 46 COVID-19 patient group compared to the 53 individuals in the control group suggesting dysregulation of macrophages, degranulation of platelets, massive metabolic suppression and complement system pathways in the COVID-19 infected group. By molecular signatures of metabolites and proteins using a machine learning model based on the expression levels of 22 serum proteins and 7 metabolites, COVID-19 severity cases can be classified [178]. 

5. Integrated Genomics and Metabolomics in Nephrology

In contrast to the estimated glomerular filtration rate (eGFR), a traditional marker, kidney biopsies, urine, and blood samples can be utilized to develop metabolomics, genomics, transcriptomics, and proteomic biomarkers. These indicators may be more strongly and precisely linked to the pathophysiologic mechanisms of the disease [179–181]. Genes and metabolites related to renal pathophysiology have been found using ‘omics’ techniques, such as metabolome analysis and GWAS. From meta-analyses of GWAS from large epidemiologic populations, several novel loci connected with the eGFR and CKD have been discovered. [182]. The implications associated with different stages of CKD include changes in the steroid hormone, glucose, NO, purine, and lipid metabolism [183,184]. The clinical utility of metabolomics in pediatric nephrology includes the identification of biomarkers, which are as of yet unidentified biological therapeutic targets, the linking of metabolites to pertinent standard indices and clinical outcomes, and the opportunity to study the intricate interactions between genetic and environmental factors in particular disease states [185]. The mechanism of metabolites and metabolic ratios associated with alteration in kidney functions are an accumulation of metabolites in response to impaired renal function mainly in the tubular cells, urine, or blood, e.g., creatinine, metabolites reflecting the activity of enzymes which are expressed in the kidney tissues and metabolites which contribute directly to disease progression [186]. 

5.1. CKD 

The identification of monogenic causes of CKD has been accomplished through genomic profiling, with approximately 500 genes identified so far, the majority of which have been reported in pediatric patients [187]. Approximately up to 37% of the adult cases among the adult population are attributed to inheritable kidney disease [188,189]. Numerous GWAS studies have been carried out, expanding our understanding of the genetic variations associated with CKD and the surrogate measure for renal function, eGFR [190]. One such GWAS study by Köttgen et al., conducted in 19,877 European individuals to identify the susceptibility loci for glomerular filtration by estimating the serum creatinine and cystatin C and CKD identified significant associations of single nucleotide polymorphism with CKD at the UMOD locus [191]. In a follow-up study, he confirmed that the elevated levels of uromodulin are linked with a common polymorphism in the UMOD region and are linked with the onset of CKD, and rs4293393 can be one of the factors related to the altered concentrations of uromodulin [192]. Indoleamine 2,3-dioxygenase (IDO), a crucial factor in T-cell inactivation, is increased by tryptophan and an increase in kynurenic acid and kynurenine. A tryptophan metabolite produced by gut bacteria called indoxyl sulfate downregulates renal-specific organic anion transporter (OAT) SLCO4C1. It has been linked to tubular cell failure [193]. 

5.2. Diabetic Nephropathy

One of the complications arising from type 1 diabetes (T1D) and T2D is diabetic nephropathy (DN). Its known metabolomic biomarkers include ketone bodies (3-hydroxybutyrate), sugar metabolites (1,5-anhydroglucoitol), free fatty acids, and branched-chain amino acids [194]. Engulfment and cell motility 1 gene (ELMO1) is a potential candidate for causing DN, according to the results of the GWAS in Japanese patients [195]. Salem et al., in their study, identified 16 genome-wide significant risk loci in a population of about 20,000 European descent with type 1 diabetes [196]. The characteristics of DN, such as expansion and thickening of the glomerular basement membrane, result from increased expression of extracellular matrix protein and ELMO1 activity [197]. 

6. Therapeutic Management of Renal Disorder Patients with COVID-19 

6.1. Vitamins 

Vitamin D deficiency is seen in most patients suffering from CKD; its deficiency can affect the COVID-19 outcome. Vitamin D influences innate and adaptive immunity, which influences how the immune system reacts to viruses and bacteria [198]. According to previous research, even a short-term acute vitamin D shortage can cause hypertension and affect the parts of the renin-angiotensin system that cause kidney damage. Vitamin D insufficiency has repeatedly been linked to proteinuria, albuminuria, end-stage renal disease (ESRD) development, and a higher risk of death from all causes in those with CKD [199]. In some instances, anemia developed in dialysis patients can be managed by giving supplemental vitamin C intravenously or orally [200]. Reactive oxygen species (ROS) are quenched by the immune cells, which otherwise may damage the lungs. Vitamin C deficiency has been linked to weakened immunity and increased susceptibility to diseases. In symptomatic COVID-19 patients, having a strong antioxidant system to eliminate such excess ROS might be beneficial [201]. 500 mg/kg of vitamin E supplementation is found to inhibit ferroptosis in COVID-19 patients and reduce the damage that ferroptosis causes to various organs, such as the heart, liver, kidneys, stomach, and neurological system leading to inflammation ablation and viral clearance via the modulation of T cells [202]. 

6.2. Metal Supplements

In the early stages of COVID-19 infection, adding metal nutrients can enhance good immune function and be a prophylactic measure for high-risk individuals. Metal nutrients may help lower COVID-19 infection rates and rates of severe disease and fatality [203]. Zinc (Zn) has been identified to prevent the synthesis of RNA, which prevents the entry, fusion, replication, protein translation, and viral propagation of many RNA viruses [204–207]. Apart from this, zinc, when administered in the form of zinc gluconate, has been shown to reduce the duration of common cold when administered within 24 h of the onset of symptoms [207]. People with CKD, especially with nephrotic disease and uremia, have been shown to have abnormalities in Zn metabolism; this alteration in the metabolism of Zn may be due to less intake of Zn in the diet, poor intestinal absorption, increased endogenous secretion and increased urinary excretion of Zn. The reason for the deficiency of Zn in people with kidney diseases is unclear [208]. Selenium (Se) deficiency is seen in AKI or CKD and COVID-19; its deficiency also has detrimental effects in the case of various viral disorders. Supplementation of Se reduces the progression of COVID- 19. In individuals with CKD, it increases the GSH-Px, which plays an essential role in the metabolism of ROS [209,210]. In obese COVID-19 patients, reduced renal function and lower magnesium levels were linked to increased mortality rates [211]. Magnesium supplements are administered to patients with AKI and COVID-19 patients with other comorbidities [212–214]. 

6.3. Melatonin

Melatonin is a well-known antioxidative and anti-inflammatory molecule. It is used in the treatment of critical care patients to reduce anxiety, vessel permeability, use of sedation, and improve sleep quality [30]. The cost-effectiveness, minor side effects, and properties of melatonin, such as anti-viral properties, an antioxidant enzyme inducer, apoptosis regulator, immune function stimulator, and free radical scavenger, make it a potential adjuvant in the treatment of COVID-19 patients and other viral infections [215–217]. Melatonin prevents fibrosis which is a complication of COVID-19. The inflammasome activity required for COVID-19 to cause lung inflammation is blocked by melatonin [218]. Through receptor-mediated or receptor-independent biological actions, melatonin regulates mitochondrial metabolism, boosts ATP production, guards’ mitochondria from nitrative damage, and has pluripotent protective effects in the kidneys. By inactivating free radicals by the transfer of one or more electrons, it effectively reduces oxidative stress. Additionally, it reduces pro-inflammatory mediators and initiates a preventive mechanism against inflammation-related chronic injury [167,219]. Melatonin reduces kidney damage caused due to COVID-19 drugs such as the lopinavir/ritonavir combination [220]. 

6.4. Renal Replacement Therapy

About 64% of critically ill COVID-19 individuals with AKI require renal replacement therapy (RRT) as it results from aberrant electrolyte concentrations and resistance to pharmacological therapy for volume overload [34,221–223]. RRT initiation in AKI patients with complications of COVID-19 alleviates not only AKI but also COVID-19. Without critical conditions, they have no significant effect on mortality and renal recovery [224]. As a result, in patients with COVID-19-associated AKI, RRT has been widely recommended when metabolic. Fluid demands exceed total kidney capacity instead of strictly determining the need for RRT initiation based on blood urea nitrogen or creatinine levels [42]. Continuous RRT is suggested in COVID-19 patients with hemodynamic instability [223]. However, its use requires extensive training, higher complexity, time consumption, continuous antico agulation, multiple equipment, and higher cost [225,226]. COVID-19 patients with AKI are also suggested prolonged intermittent renal replacement therapy (PIRRT) due to its viability, safety, lower cost, less nursing time, flexible treatment schedules, and acceptable hemodynamical tolerability [227].

7. Conclusions 

Various pathological findings can accompany SARS-CoV-2 infection, and an AKI condition directly caused by a virus is possible but not widespread. We have a unique opportunity to develop novel therapies to delay the progression of kidney disease by understanding how COVID-19-associated AKI might worsen CKD. Patients with COVID-19 AKI have frequently shown signs of endothelial damage, microvascular thrombi, local inflammation, and immune cell infiltration; nevertheless, it is unclear whether the etiologies of COVID-19 AKI and non-COVID-19 sepsis-associated AKI differ or are comparable. It is also unclear whether direct viral infection contributes to AKI development. The exact mechanism by which COVID-19 causes kidney damage remains unclear.

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