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 Table of Contents  
Year : 2022  |  Volume : 9  |  Issue : 4  |  Page : 577-584

Pathophysiology of acute kidney injury on a molecular level: A brief review

1 Bioinformatics Centre, Dr. D. Y. Patil Biotechnology & Bioinformatics Institute, Pune, Maharashtra, India
2 MIT School of Bioengineering Sciences & Research, MIT Art, Design and Technology University, Pune, Maharashtra, India

Date of Submission14-Sep-2022
Date of Acceptance02-Nov-2022
Date of Web Publication29-Dec-2022

Correspondence Address:
Dr. Vasudha Sakharam Satalkar
Department of Science and Technology, Women Scientists Scheme – A Bioinformatics centre, Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Mumbai-Bangalore Highway, Tathawade, Pune 411033, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/mgmj.mgmj_161_22

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Acute Kidney Injury (AKI) is a clinical condition with various etiologies. It is also known as acute renal failure, which is a sudden episode of kidney failure or kidney damage that happens within a few hours or a few days in patients. It causes an increase of waste products in blood and makes it hard for the patient kidneys to keep the right balance of fluid in the body. It can also affect other vital organs such as the brain, heart, and lungs. AKI is common in patients who are in the hospital, in intensive care units, and especially in older adults. It results in increased accumulation of a nitrogenous surplus in blood and a reduction in urine volume. The pathophysiology of various types of AKI is different. The earlier we can identify the causes the more effective treatment can be administered. This review attempts to identify changes on a molecular level during different stages of the disease and further discussed understanding the pathophysiology of AKI to find important molecules involved in various metabolic pathways, various phases and types of AKI, and the effect of drugs on kidneys and cellular level changes. This review article would help to design new drugs and the consequences of their metabolites to avoid Acute Kidney Injury.

Keywords: Acute kidney injury, AKI pathogenesis, molecular entities

How to cite this article:
Satalkar VS, Swamy K V. Pathophysiology of acute kidney injury on a molecular level: A brief review. MGM J Med Sci 2022;9:577-84

How to cite this URL:
Satalkar VS, Swamy K V. Pathophysiology of acute kidney injury on a molecular level: A brief review. MGM J Med Sci [serial online] 2022 [cited 2023 Feb 7];9:577-84. Available from: http://www.mgmjms.com/text.asp?2022/9/4/577/365972

  Introduction Top

Acute renal failure (ARF) has now been renamed Acute kidney injury (AKI) by Medical Dictionary for Regulatory Activities terminology (MedDRA).[1] It is a clinical syndrome where there is a rise in nitrogenous substances like urea and creatinine in the blood, which may be reversed.[2] Kidneys are unable to maintain electrolyte balance and fluid homeostasis.[3] There is a rapid decrease in glomerular filtration rate (GFR) that is linked with a reduction in the amount of blood flowing to the kidneys termed “Renal Blood Flow (RBF).”[4] The current definition of Acute Kidney Injury is “a rapid decline in the glomerular filtration rate (GFR) resulting in the retention of nitrogenous wastes, primarily creatinine and blood urea nitrogen.”[5] AKI is a broad clinical disease that encompasses various etiologies, that includes kidney diseases like acute tubular necrosis, acute interstitial nephritis, and glomerular and vascular renal injuries.[2] Conditions like ischemia (restriction in blood supply to tissues, causing a shortage of oxygen that is needed for cellular metabolism), and toxic injury are the common cause of AKI. Pre-renal azotemia (high level of nitrogenous products like urea and creatinine in the blood) and acute post-renal obstructive nephropathy are considered types of AKI as well.

AKI is a multifactorial clinical syndrome with multiple pathways and etiologies with a high mortality rate. Clinical trials so far have shown that targeting a single mechanism may not be enough to provide significant benefits. Unfortunately, none of the clinical trials have so far been translated into a therapeutic option for human AKI.[6]

Therapeutic targets and drugs for AKI currently in clinical trials as per the Therapeutic Target Database[7] are shown in [Table 1].
Table 1: Targets and entities in clinical trails

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To study molecular structural features of importance causing AKI extensive literature survey was conducted and online resources were searched. A brief abstract of the literature review is given below.

  Types of acute kidney injury Top

The etiologies of various types of AKI are explained in [Figure 1]. There are three types of AKI —pre-renal caused due to the hypo-perfusion of the kidney, intrinsic renal injuries caused due to disruption of normal physiological processes inside the kidneys, and impediment of urine flow away from the kidney called post-renal AKI. Although AKI is caused due to several factors pre-renal and post-renal AKI starts with alterations in the functional processes which are controlled at the right time and can limit remaining renal damage. Intrinsic AKI, however, causes structural damage to the kidney which is difficult to repair. Though, all these processes are interdependent AKI starts with pre-renal injuries.[2],[8],[9]
Figure 1: Etiologies of various types of acute kidney injury

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AKI is a multifactorial clinical syndrome with multiple pathways and etiologies with a high mortality rate. Clinical trials so far have shown that targeting a single mechanism may not be enough to provide significant benefits. Unfortunately, none of the clinical trials have so far been translated into a therapeutic option for human AKI.[6]

Therapeutic targets and drugs for AKI currently in clinical trials as per the Therapeutic Target Database[7] are shown in [Table 1].

  Drugs and kidney Top

The damage to the kidney due to the use of drugs is observed in the glomerular region, interstitial as well as tubular cells. The primary function of the kidney is to concentrate and reabsorb glomerular filtrate. This exposes them to high levels of drugs, their metabolites, and other toxins flowing through the fluids. Renal toxicity can be a result of changes in the flow of blood through the kidney, damage to the cells and tissue of the kidney, inflammatory processes triggered due to an injury, and obstruction of the flow of urine.[6],[9],[10]

Kidneys become the target organ in our body containing a high volume of drugs and their metabolites as their primary function is to filter the fluids flowing through them. Drugs are first metabolized in the liver and then the unabsorbed drugs or their metabolites pass into the kidney where they are reabsorbed. If these drugs or their metabolites have the necessary charge and size],[ they can pass through the glomerulus and enter renal tubular epithelial cells via pinocytosis or endocytosis.[11] Some drugs may be transported into renal tubular epithelial cells by Organic Anion Transporters called OATs or Organic Cation Transporters called OCTs that flow into the lumen of the tubules. Water is reabsorbed when the tubular fluid passes through the loop of Henle. This increases the level of drugs or their metabolites which may be injurious to kidneys. The multidrug resistance-associated protein 1 (MRP1), belongs to the ATP (Adenosine Tri-Phosphate) -binding cassette family of proteins that play an important role in modulating the absorption, distribution, metabolism, excretion, and toxicity of drugs.[12] Genetic polymorphism of transporter proteins may be responsible for different patient responses to the same drug.[13] The high level of metabolic activity in the tubular cells and the collecting duct and loop of Henle creates a hypoxic environment. Kidneys contain the enzyme Cytochrome P450 and other enzymes that oxidize drugs into lower molecular weight metabolites suggestive of the role of Reactive Oxygen Species (ROS) in renal toxicity.[12] The acidic pH of the urine helps in the crystallization of drugs and their metabolites like methotrexate. The general mechanisms of kidney injury due use of drugs are explained above. However, most drugs have unique pathways that can injure kidneys. Drugs can also induce renal dysfunction via multiple processes.

Nephrotoxic drugs have been shown to cause acute kidney injury (AKI) in 19–25% of critically ill patients.[14] These drugs injure kidneys either by their hemodynamic effect, direct cellular toxicity, osmotic cellular damage, or precipitation/crystallization or interstitial damage. Drugs are an essential component of modern healthcare management.[14] The drug is generally an organic molecule that activates or inhibits the function of a biomolecule such as a protein called receptors or targets located in the organism (pathogen) or host organ, which in turn results in a therapeutic benefit to the patient.[15] Drugs are prescribed to produce therapeutic effects but they often produce unwanted effects that range from trivial (e.g. nausea) to fatal (e.g. aplastic anemia) termed as Side effects, Adverse Drug Effects (ADE), or Adverse Drug Reactions (ADR). These terms are generally used interchangeably though they have slightly different meanings.[11]

Literature suggests that AKI is connected with drugs like non-steroidal anti-inflammatory drugs (NSAIDs), angiotensin-converting enzyme inhibitors (ACEis) [or angiotensin receptor blockers (ARBs)], cancer chemotherapeutics, antimicrobials, diuretics, etc. Understanding the underlying phenomenon on a molecular level is important in determining the most effective strategies for the treatment and/or prevention of these toxic effects of drugs.[16] This study aims to investigate reported renal adverse effects of drugs and find the molecular basis of drug-induced Acute Kidney Injury.

It is very difficult to ascertain if renal toxicity has been caused due to use of drugs. Subtle renal damage like acid-base abnormalities, water or electrolyte imbalances, and mild urinary sediment that could be found due to the use of common medications are not detectable at an early stage till an obvious change in renal function is seen usually by an increase in serum creatinine levels in the blood. Minor injury or damage to kidney function expressed by a small increase or decrease of serum creatinine (sCr) levels in blood along with the amount of urine output (UO), is a predictor of serious clinical consequences. Currently, three criteria have been established to measure the extent of kidney damage based on serum creatinine and urine output viz. RIFLE (RIFLE defines three grades of increasing severity of ARF (risk, injury, and failure, respectively, R, I, and F) and two outcome variables (loss and end-stage kidney disease, respectively, L and E), AKIN: Acute Kidney Injury Network, and KDIGO: Kidney Disease: Improving Global Outcomes.[17]

Many biomarkers have been established by researchers to predict various renal injuries and have been reviewed by Fuchs and Hewitt.[18] Some of these have been listed in [Table 2].
Table 2: Genes provided by althea DX4 for the qPCR-based detection of renal insult in Rat

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Of the many processes taking place kidney, important ones include blood flow through the renal artery, filtration via glomeruli, formation of fluids in the tubules, and excretion of the urine via urogenital organs. The number of native molecules like angiotensin II, thromboxane, catecholamine, nitric oxide, and adenosine maintains the normal human physiology viz. afferent arteriolar tone via tubuloglomerular feedback system by the juxtaglomerular apparatus, Neuro-hormonal activation of the renin-angiotensin-aldosterone system (RAAS) controls the efferent tone by angiotensin II. A trans-glomerular pressure gradient of approximately 10 mm of mercury and normal blood pressure ranges maintains the afferent or efferent tone and glomerular perfusion maintains the normal physiological processes in the kidney.[19],[20]

The mechanisms of tubular injury may be glomerular hypo perfusion, oxidative stress, inflammation, and immune dysregulation. [Figure 2] illustrates the pathways to tubular injury due to toxic or ischemic insult in AKI.
Figure 2: Pathophysiology of acute kidney injury

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  Phases of acute kidney injury Top

The major events taking place during various stages of AKI have been considered to consist of four phases. The first phase called the “Initiation phase” is the result of the reduction in blood flow through the kidney due to the reduced availability of adenosine triphosphate which causes cytological changes to the epithelial cells of the renal tubules. This phase is the start of the production of substances like chemokines or cytokines to respond to the injury. As the reduction in the level of oxygen continues the cells lining renal blood vessels get damaged and the epithelial cells start dying by apoptosis as well as necrosis. To stop this process body produces anti-inflammatory molecules, this phase is called the “Extension phase”. During the next phase called the “Maintenance phase” repair of the cellular changes and reduction in the inflammation takes place. The “Recovery phase” is characterized by epithelial cells of the renal blood vessels regaining their original structure and function.[5],[9]

The initiation phase

The initiation phase of the injury starts when the reduction in renal blood flow (RBF) reaches a level that can cause a reduction in cellular ATP availability which can cause acute cell injury and dysfunction. Epithelial cells lining the renal tubules are injured during the “Initiation Phase” of the injury. The normal structure of the cell wall is altered with the formation of f-actin (filamentous actin). These structural changes impair the normal functioning of epithelial cells of the renal tubules and endothelial cells lining renal blood vessels which in turn affects the renal vasculature. These structural damages cause up-regulation of chemokines and cytokines that results in the next phase of the injury with an inflammatory cascade.[5],[9]

The extension phase

The two major events of the extension phase are (i) continued hypoxia and (ii) an inflammatory response. The effect of both these events is observed in the outer medullary region, of the kidney. The damage to the endothelial cells lining renal blood vessels poses constraints on the blood supply to tissues, resulting in the depletion of oxygen and glucose levels needed for cellular metabolism. The inflammatory response is also observed during this phase. The outer medulla is the most affected region where cell death occurs via apoptosis as well as necrosis. In the region of the kidney where blood flow returns to normal like the cells of the proximal tubule or the cells of the outer cortex, cells repair themselves and cell morphology can improve. These structural changes can reduce the glomerular filtration rate. As the inflammatory process proceeds further the production and release of chemokines and cytokines increase. Intersecting this inflammatory process may be a possible opportunity for therapeutic intervention. However, there is a short window to produce any significant effect. Studies on animal models have shown that inflammatory cells are produced within 24 hours of injury and leucocytes may be seen within 2 hours of ischemia.[5],[9]

The maintenance phase

The phase of the injury known as the maintenance phase is associated with cell repair, migration, apoptosis, and proliferation. The cells and the blood vessels regain their original structure. The GFR is levels are adjusted depending on the strength of the original injury. The cellular changes during the maintenance phase help in improving the function at the cellular as well as organ levels. The flow of blood improves close to usual with epithelial cells maintaining metabolic equilibrium.[5],[9]

The recovery phase

The recovery phase enhances cellular changes. The epithelial cells regain their polarity. Functioning improves to normal at the organ as well as the cellular level. The re-establishment of the normal function of the kidney is directly related to the response at the cellular level to the injury.[5],[9]

  Pathogenesis of acute kidney injury on a molecular level within the cell Top

Cell membrane

The main site where AKI causes mutilation is the membrane enclosing the contents of the cells. The four mechanisms by which the damage occurs are 1.) alterations in the plasma membrane composition, 2.) changes in the associated proteins, 3.) changes in the actions of the enzymes situated on the membrane, and 4.) changing the signaling pattern by membrane-associated constituents. This can cause cell death by apoptosis as well as necrosis.[5],[21]

The cholesterol composition of the lipid bilayer gets altered after AKI. The important function of this bilayer is to protect the cell from further injury and develop cut resistance to further damage. There is increased expression of the FAS ligand involved in apoptosis, the expression of the protein caveolin-1 changes causing metabolic alterations, and there is a decrease in Na transporters after AKI. There is a decrease in membrane-associated alkaline phosphatase and altered expression of the zinc-dependent metalloproteinase meprin A associated with AKI.

Key proteins involved in the signaling pathway of necroptosis or inflammatory cell death are necrostatin-1, receptor-interacting protein kinase 3, and mixed lineage kinase domain-like protein. These proteins can induce plasma membrane leakage.

Pyroptosis is another form of cell death that differs from apoptosis. This form of cell death is caused by enzymes Caspase-1 and -11. During pyroptosis, DAMP (Damage-Associated Molecular Pattern) molecules and inflammation-producing cytokines are produced that facilitate cell damage. Another form of cell death called ferroptosis has been observed. During in vitro as well as animal testing, it has been seen that small molecules that block ferroptosis protect the cytoplasm.[22]


The structures of the nucleus that are key targets that help in AKI progression are DNA and chromatin, transcription factors, and epigenetic regulators of gene expression. The important transcription factors that are responsible for the pathogenesis of AKI via the regulation of genes include Nuclear Factor Erythroid 2–Related Factor 2 (Nrf2), the Activator Protein 1(AP-1) family, Nuclear factor kappa B (NF-κB), hypoxia-inducible factors, and Specificity Protein 1 (Sp1). The transition from acute kidney injury to chronic kidney disease is due to epigenetic modifications importantly the microRNAs. The highly expressed enzymes in kidney deoxyribonuclease I and endonuclease G along with other oxidants can mutilate the DNA. These enzymes are responsible for the acute tubular injury.[23],[24]


Actin is the key molecule in the cytoskeleton that modulates the pathogenesis of AKI. The changes in actin composition changes in polarity of the cells, cell-cell interactions, and cell-matrix integrity which in turn affects the function of the tubules changing the glomerular filtration rate.[5]

Endoplasmic reticulum

The endoplasmic reticulum (ER) is continuous with the outer membrane of the nucleus. The accumulation of unfolded proteins can cause ER stress during AKI. The pathway identified to cause ER stress during AKI is the Protein Kinase RNA-Like Er Kinase (PERK)- Activating Transcription Factor 4(ATF4)- CCAAT/Enhancer-Binding Protein Homologous Protein (CHOP) pathway. The important constituents of this pathway are the enzyme PERK- protein kinase RNA-like ER kinase; the transcription factor ATF4 - activating transcription factor 4 and CHOP – Cytosine-Cytosine-Adenosine-Adenosine-Thymidine Box Motif (CCAAT)/enhancer-binding protein homologous protein.[24]


Mitochondrial pathology is common to all forms of AKI including renal ischemia, sepsis, and nephrotoxic injury. The characteristics of mitochondrial damage are swelling with a change in the folding pattern of the cristae and mitochondrial disintegration.[25],[26],[27],[28],[29],[30],[31],[32]

In response to hypoxia, there is an increase in the concentration of calcium in the cytoplasm, alteration in the ratio of Nicotinamide Adenosine Dinucleotide (NAD)/ Nicotinamide Adenine Dinucleotide - Hydrogen (reduced) (NADH)

NAD/NADH, reduction in voltage across the mitochondrial membrane, oxidative stress, and other toxic stimuli. Mitochondrial involvement in cell death is not only via a decrease in the amount of Adenosine Tri Phosphate but also via two other separate mechanisms one depending on Reactive Oxygen Species (ROS) and the other involving mitochondrial permeability transition (MPT). The damaged mitochondria turn out to be a rich source of ROS. These ROS can be targeted by antioxidants like MitoQ or by binding to antioxidant peptide SS-31. The MTP pore is composed of several proteins and is found in the inner matrix of mitochondria under the conditions of oxidative stress. When it opens, the contents of mitochondria and cytoplasm mix with each other. This releases mitochondrial calcium into the cytoplasm, which can activate proapoptotic mediators like cytochrome C. Consequently, there is swelling of the mitochondria which can cause the mitochondria to disintegrate.[25],[26],[27],[28],[29],[30],[31],[32]

The number of mitochondria in a cell is maintained by a balance between generative (biogenesis) and destructive/recycling (mitophagy) processes. The involvement of transcriptional coactivators PGC1α has been established in mitochondrial biogenesis in literature. PGC1α (peroxisome proliferator-activated receptor gamma coactivator 1 alpha) is expressed in cortical epithelial cells and is responsible for mitochondrial abundance. However mitochondrial fission has been observed more than fusion in the AKI setting. Dynamin-related protein 1 (DRP1) starts the process of mitochondrial splitting. Targeting the DRP1 protein improves mitochondrial integrity in vitro. The ROS generated during AKI increases the probability of the addition of the proapoptotic protein Bax, or other processes.[25],[26],[27],[28],[29],[30],[31],[32]

The process of mitophagy helps in the removal of injured mitochondria. The process is linked intricately with the subtleties of fission and fusion of cells. During mitochondrial division, if the mitochondrion of a daughter cell loses membrane potential, it may be removed by mitophagy. Thus, this process helps to maintain the characteristics of mitochondria in a cell. During AKI the rate of fission is greater than the rate of fusion, therefore mitophagy is a useful process to clear fragmented mitochondria. The important molecules involved in the process of mitophagy are sestrin-2 and BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3) BNIP-3 in the acutely injured kidney been reported by researchers. The proteins mitofusin 1, and mitofusin 2 (Mfn2) found in the outer membrane, along with optic atrophy protein1 (OPA1) control the process of mitochondrial fusion.[25],[26],[27],[28],[29],[30],[31],[32]


The receptors Fas Cell Surface Death Receptor (FAS) receptor and Transforming Growth Factor Beta (TGFβ) receptor have been identified to play a major role in causing AKI. The receptors Epidermal Growth Factor Receptor (EGF) receptor, HGF receptor C-Met, also called Tyrosine-Protein Kinase Met Or Hepatocyte Growth Factor Receptor (HGFR) (C-Met), sphingosine-1-phosphate receptor, and netrin-1 offer protection to the epithelial cells during AKI.[21]

Cell cycle

The cell cycle consists of 4 stages viz. G1 – gap1, S- synthesis, G2 – gap2, and M- mitosis, are responsible for cell proliferation. In AKI, damaged renal tubule cells proliferate rapidly. This is because when the tubular cell of the kidney becomes injured, they die and are shed into the lumen, neighboring cells may increase in size to cover the bared area, become de-differentiated, and activate the cell cycle. These cyclins and cyclin-dependent kinases (CDKs) have been identified to drive this process. However, the cell cycle inhibitors CDK-interacting protein 1 (CIP1), p21 binds and antagonizes cyclin-CDK complexes, halting the cell cycle during the G phase. The molecule p53 is induced via the DNA damage response mediated by Ataxia Telangiectasia and Rad3-related protein (ATR) / Checkpoint Kinase 2 (Chk2) signaling pathway. p53 may also be responsible for the transcription and expression of p21 which can halt the cell cycle. Urinary levels of insulin-like growth factor binding protein-7 and tissue inhibitor of metalloproteinase-2 are both inducers of G cell cycle arrest and are important biomarkers in human AKI.[33]


The enzymes called cathepsins are released during lysosomal disruption. They may cause lysosomal cell death. Autophagy is a process that transports cytoplasmic constituents to the lysosome for disintegration and reprocessing. The molecule p53 may cause autophagy as per literature. Oxidative stress may also cause autophagy. The autophagy genes, viz. Atg5 and Atg7 induce autophagy and enhances kidney injury.[5],[21]


Peroxisomes are tiny cellular structures in the cytoplasm of a cell that contain many enzymes that catalyze many reactions. Therefore, they are highly metabolically active organelles that can regenerate tubular epithelial cells. Thus, peroxisomes protect the setting of AKI. The overexpression of the Sirtuin Family (Sirt1), a NAD-dependent protein deacetylase regulates metabolism within the cells and reduces Reactive Oxygen Species and cell death caused by them. The peroxisomes offer a protective effect in the setting of AKI.[5],[6],[21]

  Conclusion Top

Given the multiple overlapping pathways involved in AKI, therapies may need to simultaneously target multiple pathways to achieve success. Also, patient-related risk factors like age, sex, patients with pre-existing renal dysfunction, diabetes, patients with congestive heart failure, multiple myeloma, cirrhosis, sepsis, sodium-depleted patients, acid-base disturbances, hypo-albuminuria, concomitant use of other nephrotoxic drugs need attention in managing AKI.[34] Drugs-producing intermediates involved in the urea and creatinine cycle can also cause injury to the kidney.

The above study has identified the functions of important molecules, proteins, receptors, enzymes, transporters, pathways, and genes/transcription factors involved in the pathophysiology of AKI. It will be used in the subsequent stage of the project to compare with the metabolism of drugs causing Acute Kidney Injury. This study will further guide the Pharma industry in designing various drugs for conditions like ischemia, sepsis, and toxicity and find new ways to deal with the complex mechanisms involved in AKI.

The various proteins, receptors, genes, etc. identified from this study can be investigated as potential targets using bioinformatics methods like Quantitative Structure-Activity Relationship models. Using molecular docking studies to come up with molecules that can be used as drugs to cure AKI. The best molecules identified can be subjected to molecular simulation studies to find the stability of the drug and target interaction.

This study indicates that there are opportunities for researchers from other disciplines with an interest in kidney disease to collaborate on research. This will enhance our body of knowledge in this important area.


The authors are thankful to the Department of Science and Technology, New Delhi, India for providing funds under the Women Scientists Scheme – A Project Reference No.: SR/WOS-A/LS-494/2017 to carry out the research work and Dr. D.Y. Patil Vidyapeeth, Pune, Maharashtra, India for infrastructure facilities.

Financial support and sponsorship

This work was supported by the Department of Science and Technology, New Delhi, India.

Conflicts of interest

There are no conflicts of interest.

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  [Figure 1], [Figure 2]

  [Table 1], [Table 2]


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