COVID-19: Associated Acute Kidney Injury (AKI) Pathology and Therapies from Complementary and Alternative Medicine

: More frequently than first believed, kidney involvement after SARS-CoV-2 infection is linked to morbidity and mortality. Similar to the etiology of other types of AKI, the pathophysiology of COVID-19 AKI is most likely complex. Although rates of COVID-19 AKI vary significantly across studies and geographical areas, the information currently available points to an incidence of > 20% in hospitalized patients. There are several similarities between COVID-19 AKI and AKI resulting from non-viral causes observed in the ICU, including risk factors, potential processes, and prognosis. Despite noticeably decreased kidney function, acute tubular damage is frequently present, even though it is often minor. Tubular damage most likely results from systemic hemodynamic instability. Despite COVID-19 being referred to as a cytokine storm syndrome, patients with COVID-19 frequently have lower amounts of circulating cytokines than those with acute respiratory distress syndrome from causes other than COVID-19. The prevention and treatment of COVID-19 AKI are poorly understood. Regional'surges in COVID-19 cases might restrict hospital resources, particularly the availability of supplies for dialysis; as a result, thorough daily monitoring of the resources at hand is required. Based on the most recent research, the Acute Disease Quality Initiative recommends diagnosing, preventing, and managing COVID-19 AKI in this Consensus Statement. Additionally, we sought to enhance comprehension of the underlying mechanisms and enhance patient outcomes for COVID-19 AKI. It is essential to comprehend the core molecular mechanisms and the pathophysiology of kidney damage and AKI in COVID19 to create appropriate management plans and therapeutic designs.


Introduction
A brand-new coronavirus called the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was found in China in December 2019.The coronavirus disease 2019 (COVID- 19), which is brought on by this virus, is characterized by diffuse alveolar destruction that results in an acute respiratory distress syndrome [1].Although acute kidney injury (AKI) is now recognized as a prevalent consequence of the disease and is frequently seen at hospital admission, the pulmonary signs of COVID-19 are still the most conspicuous.Initial reports from China claimed kidney involvement rates were relatively low [2][3][4], but later findings from the USA and Europe show that AKI rates are significantly higher [5][6][7][8].In addition, compared to individuals with normal kidney function, these patients displayed lower platelet and lymphocyte counts, greater leucocyte counts, a higher risk of comorbidities, and a requirement for intensive care.However, mounting evidence suggests that AKI is very common among COVID-19 patients, particularly those in the intensive care unit (ICU) [9].Although the reported rates of AKI are pretty variable, the information that is now available indicates that it probably affects more than 20% of hospitalized patients and more than 50% of ICU patients [9,10].Similar to how AKI is linked to other types of pneumonia acquired in the community [11].The pathophysiology of renal disease in people with COVID19 may entail a variety of causes [12,13].The angiotensin-converting enzyme 2 (ACE2), which serves as a SARS-CoV2 receptor, may be directly involved in the virus's first effects on the renal parenchyma.The genes for ACE2 and transmembrane protease, serine 2 (TMPRSS2) are expressed in kidney cells at levels comparable to those seen in the lung, small intestine, and esophagus, indicating their significance as SARS-CoV2 targets [14].
Furthermore, current research points to podocytes and proximal convoluted tubules expressing the ACE2 gene as significant SARS-CoV2 host cells, suggesting that the renal tissue may be a potential SARS-CoV2 target [15].Beyond its role as a viral receptor, ACE2 may link the renin-angiotensin system (RAS), the kallikrein-kinin system, and COVID-19 (KKS) [16,17].In this review, we first discuss the dispute surrounding SARS-CoV-2 and its direct function in kidney infection.We then define AKI in COVID-19 based on the injury pattern and thoroughly characterize all documented histological abnormalities.

COVID-19
A pneumonia outbreak with an underlying etiology was reported in December 2019 in Wuhan, Hubei Province, China.The subgenus Sarbecovirus includes the betacoronavirus SARS-CoV-2.The outbreak has cost the world extensively regarding lost human lives, adverse economic effects, and rising poverty [18].A polybasic cleavage site at the S1/S2 spike junction regulates infectivity and host range and the virus's optimum affinity for the angiotensin-converting enzyme 2 (ACE2) receptor, which are two traits that distinguish SARS-CoV-2 from other coronaviruses.[18][19][20].Although other organ systems are also affected, the SARS-CoV-2 virus principally affects the respiratory system [21,22].The earliest case series from Wuhan, China, reported lower respiratory tract infectionrelated symptoms such as fever, dry cough, and dyspnea.Other symptoms, e.g., such as vomiting, diarrhea, headache, and widespread weakness, were noted [22,23].It is now commonly acknowledged that COVID-19's respiratory symptoms are incredibly diverse, ranging from hardly noticeable symptoms to severe hypoxia with Acute Respiratory Distress Syndrome (ARDS) [22].Coronaviruses are positive-sense, single-stranded, enclosed RNA viruses about 30 kb in size [24].Various host species are infected by them [25].Based on their genetic structure, they are generally split into four genera: α, β, γ, and δ.Only mammals can get infected by α and β coronaviruses [26].The common cold and croup are caused by human coronaviruses like 229E and NL63, which are in the coronavirus family [22].Four structural proteins are found within coronaviruses: spike (S), membrane (M), envelop (E), and nucleocapsid (N) [27].Spike a transmembrane trimetric glycoprotein that protrudes from the virus's surface and controls host tropism and coronavirus diversification [22,27].Spike comprises two functional subunits: the S1 subunit binds to the host cell receptor, and the S2 subunit joins the viral and cellular membranes.SARS-CoV functional receptor angiotensinconverting enzyme 2 (ACE2) has been identified [28].The spike for SARS-CoV-2 also linked to ACE2, according to structural and functional studies [29][30][31].ACE2 was highly expressed in ileum, kidney, bladder, lung, and heart [32].The lower respiratory tract in humans can be affected by coronaviruses.These potential pathogens can cause illnesses ranging from a simple cold to severe infections with up to 50% mortality [33,34].COVID-19 presents an acute upper and lower respiratory tract infection that develops into pneumonia and impacts numerous other tissues and organs, including the kidneys [35,36].The most common symptoms were fever, coughing, acute exhaustion, viral illnesses, and pneumonia.[1,36,37].Although most patients have a mild form of the disease, some patients can develop respiratory failure, arrhythmias, shock, kidney failure, cardiovascular damage, or liver failure, especially if they suffer from other diseases [36,38,39].According to a current study, fever, cough, and extreme tiredness were present in 81.2%, 58.5%, and 38.5% of cases, respectively [34].The most prevalent symptom in COVID-19 patients is a fever, though still, not all individuals experience this.Vomiting and fever (over 39 degrees) are typically indicators of more severe sickness and a more extended hospital stay, but fever is a concerning indicator of the illness [21,36,40].Vomiting and fever (over 39 degrees) are typically indicators of more severe sickness and a more extended hospital stay, but fever is a concerning indicator of the illness [34,36].Although COVID-19 cannot be detected early on by the immune system, research and clinical evidence indicate that SARS-CoV-2 may be colonized in the nasopharynx.Sneezing and runny nose are two examples of how the body might naturally rid itself of the infection.Patients with COVID-19 exhibit a wide range of impairments and organ dysfunctions.Depending on the patient, the disease's progression varies from asymptomatic infection to severe symptoms and even fatal events [41][42][43].Pathological alterations in the kidney during COVID-19associated AKI include tubulointerstitial, glomerular, and vascular destruction [43].A study finds out that the kidney image shows extensive injury in the proximal tubule with brush border loss and severe necrosis, as well as vacuolar degeneration and tubulointerstitial fibrosis [43].SARS-CoV-2 viruses are visible in the tubular epithelium using electron microscope imaging, especially in the proximal tubule and podocytes [42][43][44].Infiltrate is formed by inflammatory cell types, and edema can be noticed in the interstitial compartment [43].Infiltrating inflammatory cell types and edema can be detected in the interstitial compartment.The basement membrane is the only obstacle between the filtrate and the peritubular interstitium in the severe case of kidney injury.Due to elevated endothelial permeability, glomerular filtrate spills into the interstitium from the tubular lumen [44].Autopsies from the kidneys of COVID-19 patients have shown diffuse and focal segmental fibrin thrombus in the glomerular capillary loops and endothelial damage [43].Collapsing glomerulopathy is characterized by loss of podocyte integrity and glomerular epithelial degeneration.Glomerular capillaries become segmentally or universally collapsed and dysfunctional due to hyperplasia and hypertrophy of the glomerular epithelium.[43].A reduction in GFR and an increase in SCr are indicators of further damage.The baseline functional reserve is constrained by underlying chronic renal disease or aging-related variables, which might accelerate the onset of acute kidney injury (AKI) [45].

Acute Kidney Injury
Acute kidney injury is referred to as damage to the kidney tubule cells.Evidence to date shows that acute kidney injury was the primary cause of the great majority of AKI cases in COVID-19 individuals and the main pathological finding in Acute kidney injury [46].The study of kidney autopsy and kidney Histopathology also indicates that acute kidney injury was observed in the kidneys of individuals who had severe COVID-19 infection and died [47,48].From a kidney histopathology survey of 42 individuals who died from COVID-19, One of the most important discoveries was a mild acute kidney injury.Acute kidney injury may occur due to Long-term volume depletion and hemodynamic conditions that lower kidney perfusion.When COVID-19 is severe, immune cells are recruited by the viral infection in type II alveolar cells, which produces an excess of cytokines that might cause circulatory collapse [49].Kidney injury is also likely caused by systemic hemodynamic instability and increased renal interstitial pressure brought on by tissue edema.The kidney damage caused by SARS-CoV-2 is anticipated to be complex; it can be directly infected by Podocytes and proximal kidney cells [50].Acute kidney injury and diminished glomerular filtration rate (GFR) are related, this relation between them gives rise to three potential ways that the renal tubular epithelial cells might be damaged: [51] 1) Tubuloglomerular Feedback induces afferent arteriolar vasoconstriction.2) Glomerular filtrate leakage backward.
3) Blockage in the tubes.Some symptoms of acute kidney injury due to COVID-19 are splenic infraction or showing signs of hematuria and loin discomfort.Circuit clotting is more often in COVID-19 patients receiving hemodialysis [52].Treatment of acute kidney injury may include preventing hypovolemia or hypotension; patients with low blood pressure should stop using ACEI or angiotensin II receptor blockers.Additionally, intravenous (IV) fluids such as crystalloids should be used to optimize volume status and maintain appropriate renal blood flow.Medications that can lead to acute kidney injury, such as Nephrotoxic medications (NSAIDs), and antibiotics, such as vancomycin and radiocontrast agent, should be avoided [51].For the treatment of acute renal damage, Renal Replacement Therapy (RRT) may also be the preferable option.In conclusion, acute kidney injury appears in individuals inevitably in the presence of severe COVID-19, but it is frequently moderate despite severely compromised kidney function [53].
Collapsing glomerulopathy is also associated with acute kidney injury in patients with COVID-19 [54], and It typically goes together with acute kidney injury, kidney dilation with microcyst formation, and interstitial inflammation [55].Collapsing glomerulopathy (CG) is a severe and distinctive histologic variation of focal segmental glomerulosclerosis defined by segmental or global glomerular cluster breakdown, along with overlaying podocyte enlargement and proliferation [56].Collapsing glomerulopathy was First discovered in the context of HIV infection and later became known as the typical Histomorphology type of HIV-associated nephropathy (HIVAN) [67].

COVID-19-Associated AKI Pathophysiology
The lungs are the most known affected organ by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).Entry of this virus is regulated by the help of ACE2angiotensin-converting enzyme 2, expressed in the lungs, heart, brain, intestine, liver, pharynx, and other tissue [58].But among, various organ abnormalities, dysfunctional syndromes, and cardiac and renal functional disturbance are the prevalent symptoms present in patients who die from COVID-19 [69].AKI (acute kidney injury) is a clinical marker of faster decline in kidney activity due to the effect of various inducers.It is closely associated with health problems and death [60].The invading viruses may infect the lungs, travel via the bloodstream, and infect the kidneys, where they might build up and harm local cells.
Consequently, the kidney is one of the extrapulmonary organs that is frequently affected [61].Therefore, COVID-19 is a threat by itself and affects patients suffering from renal abnormalities in a worsened way.A study in New York showed that 454 of the 5700 hospitalized COVID-19 patients had the renal illness.Five hundred fifty-three patients faced death out of the 5700 patients, while 81 were administered renal replacement treatment [62].Another study showed that 8.3% of patients suffering from AKI and COVID-19 in Wuhan Zhongnan Hospital were admitted to ICU out of the 138 patients, while only 2% were non-ICU patients [63].Typically, COVID-19-induced kidney injury shows up as tubular destruction and evident urinalysis abnormalities.In addition, it is usually associated with a rise in creatinine and urea nitrogen level.Abnormal glomerular filtration is also visible in patients [35].One study conducted among 59 patients (COVID-19 affected) visualized that the creatinine level was higher in 19% of patients, while 27% had elevated urea nitrogen levels [64].From this, it can be seen that understanding the clinical characteristics of COVID-19 infection with kidney damage is crucial to the prevention and treatment of COVID-19.
Critically sick patients frequently develop acute kidney damage (AKI), linked to significant health problems and mortality.Although COVID-19s primary symptoms are respiratory failure, pulmonary manifestation, or hypoxia, renal abnormalities are frequently seen.Studies have prioritized observing different respiratory complications during the onset of the new SARS-CoV-2 pandemic.Consequently, less attention was given to AKI incidence in those patients [65].But recently, much research has been conducted on AKI and its relationship with COVID-19.Several reports have now established AKI as a widespread complication of the disease.Studies showed that almost 45% of ICU patients need renal therapy [5,6] due to AKI.The pathophysiology of COVID-19-associated AKI has not been adequately elucidated yet.However, current findings from studies suggest two mechanisms: specific mechanisms and unspecific mechanisms.A Specific mechanism involves a receptor named ACE2, which is highly expressed in the kidney.Non-specific factors, for example, hypoxia, low cardiac output, hypotension, and hypertension, might contribute to this pathophysiology [66].

SARS-CoV-2 Invasion in the Kidney
A variant of ACE is called angiotensin conversion enzyme 2 (ACE2).Angiotensin 2 is changed into angiotensins 1 through 7. It reduces renin-angiotensin system activity, which induces vasoconstriction [67].ACE2 possesses a membrane-bound form associated with SARS-CoV-2 during cellular invasion [66].Cell invasion also requires the presence of a protease named Transmembrane protease, seine 2 (TMPRSS2), that can break down viral spikes [68].The RAAS (renin-angiotensin-aldosterone system) and ACE-2 play essential roles in SARS-CoV-2 infection.Renin converts angiotensinogen into angiotensin-1, which then undergoes a second conversion to become angiotensin two by ACE.As a result, the harmful repercussions of Raas activation are caused by angiotensin-2 [67].ACE-2 counteracts this negative impact.By converting angiotensin-1 into angiotensin (1-9), ACE-2 combats the harmful consequences of RAAS activation.SARS-CoV-2 invades the cellular system by forming a complex with ACE-2, which results in the declination of this membrane-bound conversion enzyme.Insufficient ACE-2 triggers aggregation of angiotensin-II, which causes the RAAS to be imbalanced, increasing inflammation, fibrosis, and vasoconstriction [66,69].According to mounting proof, inflammatory cytokines are raised in severe COVID-19 patients, primarily when referred to the intensive-care unit.In severely ill patients, IL-2, IL-7, IL-10, G-CSF, IP10, MCP1, MIP1A, and TNF-α levels were greater [21].Via associating with renal native cells and triggering endothelial and tubular malfunction, these peptides may promote AKI in COVID-19 patients.Example: IL-6 concentrations in critically ill COVID-19 individuals have been confirmed excessive in some investigations [70].Variants of AKI, such as ischemic AKI, nephrotoxin-induced AKI, and sepsis-induced AKI, have demonstrated that IL-6 exerts detrimental impacts [71].Clinical studies showed that the corona family viruses' ability to cause glomerulopathy was minimal; however, immune complexes deposition of viral particles or virus-induced particular immunological abnormalities are still possible [72].The expression of the genes for ACE2 and transmembrane protease, serine 2 (TMPRSS2) in kidney cells is comparable to that in the lung, small intestine, and esophagus, suggesting their significance as SARS-CoV2 targets.Beyond its role as a viral receptor, ACE2 may link the renin-angiotensin system (RAS), the kallikreinkinin system (KKS), and COVID-19.When SARS-CoV-2 binds to ACE2, ACE2 activity is reduced, upsetting the physiological balance between ACE and ACE2, which results in the loss of angiotensin-(1-7protective)'s effects and an accumulation of angiotensin-II.This encourages vasoconstriction, inflammation, and glomerular dysfunction, leading to AKI [72].
The kidney can be directly infected by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which invades cells and uses the host cell's machinery for replication.SARS-CoV-2 infection of the proximal tubules is likely accompanied by the presence of virions in the urine [73].Dehydration was one of the potential contributing factors to the renal abnormalities caused by COVID-19; this condition could be brought on by a fever or by an older adult's decreased fluid intake.Dehydration affects the kidney in several ways, reducing the glomerular filtration rate and leading to acute renal damage [72].

Non-Specific Factors
There is a decent chance that some other parameters besides the virus have a role in the etiology of AKI in the scenario of COVID-19, including drug toxicity, hemodynamic parameters, and the influence of organ infrastructures.Renal hypoperfusion and acute tubular injury may emerge from acute hypoxemia's potential to interfere with renal function and increase renal vascular resistance [75,76].Patients having severe COVID-19 have quite an increased chance of AKI after getting automated ventilation [77].The cardiovascular system and kidneys are most likely to collaborate to promote COVID-19-induced AKI.Myocarditis and myocardial infarction are acute cardiovascular system abnormalities.Patients suffering from myocarditis and myocardial infarction along with COVID-19 may damage cardiac output.In addition, it may impair kidney oxygenation through a diminution of cardiac production or congestion of the renal venous system [78,79].The most obvious cause of severe COVID-19 infection in hospitalized patients is acute respiratory distress syndrome (ARDS) [80].In addition, severe hypoxemia and inadequate gas exchange have been categorized as risk factors for AKI in ARDS patients [66].Most COVID-19 patients with AKI are older and typically have coexisting conditions such as high blood pressure or diabetes mellitus [80,81].These elements have been recognized as well-known contributors to AKI development in individuals with severe respiratory failure [82].Moreover, individuals suffering from these conditions are being treated with drugs that hinder normal renal flow.This could be relevant since several patients had a persisting fever, trouble breathing, and digestive issues, leading to subsequent pre-renal AKI [21,81].

Factors Causing Acute Renal Damage Linked to COVID-19
One well-known side effect of coronavirus infection (COVID-19) is acute kidney injury (AKI).In the most seriously affected individuals, non-specific factors typical in chronically sick individuals, e.g., mechanical ventilation, hypoxia, hypotension, poor cardiac activity, and nephrotoxic drugs, may also be responsible for kidney damage and functional impairment [45].According to a multivariate assessment, the frequency of AKI was correlated with male sex, black and Asian/Native American ethnicity, greater BMI, higher APACHE IV score [83], and lesser baseline estimated glomerular filtration rate (eGFR) [84].Procalcitonin, Creactive Protein, lactate dehydrogenase, serum ferritin, aspartate aminotransferase, fibrinogen, and reactive incomplete thromboplastin duration were among the laboratory factors linked to moderate-to-severe or severe AKI and the combined result in-hospital mortality [84].
Tubular damage is caused by low molecular mass proteinuria, Fanconi syndrome, histological abnormalities, and local inflammation.In addition, even after directly contracting a virus or compartment syndrome in the kidneys, administering antibiotics or antiviral drugs may be related to nephrotoxic-induced damage [45].Another important aspect that might lead to acute kidney injury attributed to COVID-19 is vascular impairment.Endotheliitis, microthrombi, and thrombotic microangiopathy are the three factors that may lead to vascular impairment.As potential mediators of the pathophysiology and certain clinical signs of COVID-19, endothelial vascular impairment and thrombo inflammation related to SARS-CoV2 viral infections are now being identified [85].Glomeruli are at the center of renal activity, even though they make up just a small portion of a complete nephron.When it comes to preserving homeostasis, they are invaluable.Acute interstitial nephritis and immune cell infiltration are the two conditions that lead to interstitial injury.In the documented kidney biopsy reports from individuals with COVID-19, interstitial infiltrates have not often been noted [86].However, according to research, most ICU individuals with severe COVID-19 likely take many drugs linked to interstitial nephritis [87].

Various Phases of COVID-19-Associated Acute Kidney Injury
Acute kidney injury linked to COVID-19 can be separated into three stages.(AKIstage-1, AKI stage-2, AKIstage-3).AKI stage 1 involves three substages (i.e., 1S, 1A, and 1B).Stage 1S designates a preliminary stage where evidence shows kidney injury occurs but is not picked up by creatinine and urine output parameters; in this stage, biomarkers of kidney injury give positive results, but there is no change in serum creatinine level and urine output (neither increase nor decrease) [88].In AKI stage 1A, there is an increased serum creatinine (sCr) or decreased level of urine output (UO) but a negative result in biomarkers; in AKI stage 1B, there is an increased serum creatinine or decreased level of urine output with a positive result in biomarkers [88].Patients with earlystage AKI may be identified via proteinuria detection [94].The role of CKD is uncertain, but The percentage of individuals with proteinuria and COVID-19 is significantly higher than the frequency of stage 1 and stage 2 CKD in the general population [85].AKI stage 2 involves two substages (i.e., 2A and 2B).There is a rise in sCr levels of more than 200% and a UO level of lower than 0.5 mL/kg/h for more than 12 hours in this substage, but 2A has a negative Biomarker, and 2B has a positive Biomarker.AKI stage 3 can also involve two substages (i.e., 3A and 3B).There is a rise in sCr levels of more than 300% and UO levels of lower than 0.5 mL/kg/h for more than 24 hours or Anuria for more than 12h in this substage, but 3A has a negative Biomarker, and 3B have positive Biomarker [88].Analysis of postmortem kidney samples from patients with stage 2 or stage 3 AKI and COVID-19 indicated acute tubular damage, which is characterized by mostly moderate localized acute tubular necrosis [86].AKI stage 3 with COVID-19 patients is common and they carry high mortality rate.The majority of AKI stage 3 patients require kidney replacement therapy on mechanical ventilation, and 90% of individuals with stage 3 AKI who were not dialyzed died [87].Reduced vasodilation, a pro-inflammatory environment, and prothrombotic characteristics are key features of endothelial dysfunction.Patients with SARS-CoV2 infection may experience coagulation impairment for various reasons.Two basic approaches might be used to summarize them Inflammation and cytokines storm and specific-virus mechanism where "cytokine storm" seems to play a pivotal role in virusspecific mechanisms, linked to the virus's interaction with the RAS and the fibrinolytic pathway, as well as comorbidities that these individuals have [88].Possibly another virusspecific mechanism may be associated with autoimmunity development [94].
The cytokine storm may accelerate AKI in COVID-19 patients, By collaborating with renal resident cells and encouraging tubular and endothelial dysfunction [90].The activation of innate immunity led to increased levels of many proinflammatory cytokines during the SARS-CoV2 infection.and the most severe symptoms of the illness appear to be caused by the so-called "cytokine release syndrome" [91], Interleukin-6 (IL-6) has emerged as one of these cytokines with a key function, and it is now being studied in therapeutic trials using anti-IL-6 medicines to treat severe forms [92].In individuals with acute inflammatory diseases, such as sepsis and a hyper-coagulable state, elevated levels of tumor necrosis factor (TNF), IL-6, and IL-1 are detected in vivo, occasionally developing into DIC.Results from clinical trials indicate that IL-6 is the key player in cytokine-induced coagulation activation [93].
Additionally, IL-6 encourages the production of additional coagulation factors, including factor VIII and fibrinogen [94,95], releases proinflammatory chemokines and cytokines by renal endothelial cells, and, through boosting VEGF release, acts on endothelial cells to cause vascular permeability [96,97].Additionally, pro-inflammatory cytokines can cause capillary leak syndrome and thrombosis formation, which might lead to disseminated intravascular coagulation [98].According to reports, COVID-19 individuals have unusually high levels of the soluble IL-6 receptor (IL-6R) in their plasma as a result of the infection's accelerated cell surface cleavage; after then, most cells, including endothelial cells, can be directly activated by circulating complexes of soluble IL-6 and IL-6R [99].The ongoing coagulopathy brought on by infection may also contribute to thrombocytopenia, and the cytokine storm may also encourage the growth of megakaryocytes, which would lead to thrombocytosis [100].Additionally, because cytokines can activate macrophages, erythro-phagocytosis and Anemia are seen, Anemia, cytokine-induced injuries, and disruptions of vascular hemostasis all work in concert to cause renal multi-organ failure [101].

The Immune and Inflammatory Response of the Kidney Due to COVID-19
The primary symptoms of COVID-19 are hypoxia and respiratory distress; however, kidney involvement also occurs frequently.Presumably, there are several ways that viruses can infect the kidneys.Viruses can build up and sprout in glomeruli, where they may directly harm the host tissue.Furthermore, tissue antigens can passively elicit reactions, and viruses can function as a local stimulant to predispose the kidneys to microbial infection.According to contemporary research, the coronavirus penetrates cells via ACE2 and stimulates Toll-like receptors (TLRs) [107].TLRs may induce the activation of transcriptional regulators, control the production of cytokines and chemokines that promote inflammation and contribute to the innate immune reaction.It has been suggested that these receptors are crucial for the pathogenesis of kidney disease [107].Mainly AKI (Acute Kidney Injury) is linked to overstimulation of these receptors.The precise location of ACE2 and transmembrane protease serine (TMPRSS) activity and distribution in kidney cells were determined in a recent study using single-cell RNA sequencing analysis [14].Numerous mechanisms influence COVID-19-induced kidney damage, involving direct kidney damage caused by the virus and angiotensinconverting enzyme 2, aberrant immune response, a cytokine storm triggered by SARS-CoV-2 infection, organ linkages, a hypercoagulable condition, and endothelial malfunction.
Being infected with SARS-CoV-2, individuals with severe COVID-19 had considerably higher levels of neutrophils, leukocytes, and neutrophil-lymphocyte ratios than individuals with moderate COVID-19 [108].Furthermore, individuals with COVID-19 who undergo kidney biopsy show significant amounts of CD4+ T cells, CD56+ natural killer cells, and CD68+ macrophages infiltrating the tubulointerstitial [109].This situation denotes the activation of T lymphocytes, which then go toward the infection site to carry out their role.Nevertheless, SARS-CoV-2 targets tissues with an incompetent immune reaction and releases cytokine storms that cause T cells to necrotize or apoptosis, which diminishes T cells and hinders viral removal [21,110].As a result, individuals with COVID-19 are reported to have reduced lymphocyte levels and frequently have poor prognoses [111].
Furthermore, Immunoglobulin M (IgM), which binds ACE2 in kidney cells, is produced after SARS-CoV-2 infection and causes type 2 hypersensitivity responses, which drive kidney damage [109].Several investigations using renal biopsies from COVID-19 individuals demonstrate the role of autoimmunity on renal activity.IgG, IgM, and C3 accumulation were found in the glomerular filtration barrier of COVID-19 patients [112].After thoroughly analyzing kidney samples from COVID-19 individuals, Macor et al. noticed IgG and C aggregates surrounding the tubules and glomeruli [113].Correspondingly, research reveals IgA granular accumulation in the renal mesangium of COVID-19 individuals through immunofluorescence and the demise of podocytes under electron microscopy.The study hypothesized that these pathological alterations were linked to type 3 hypersensitivity reactivity brought on by antigenantibody complexes [114].
Anti-ACE2 autoantibodies in individuals can potentially disrupt the balance of ACE to ACE2, which might result in abnormalities of the renin-angiotensin system (RAS), promote tissue deterioration, and exacerbate inflammation [110].Additionally, the complement system has a role in the pathophysiology of AKI in COVID-19 [115].According to previous research, complement C5b-9 builds up at the brush borders of the apical tubules via a different mechanism after amassing in the lumen of the renal tubules, causing tubulointerstitial degeneration [116,117].According to an investigation, significant complement accumulation was seen on the renal tubules of six critically sick COVID-19 individuals whose kidneys were biopsied.This finding suggests that SARS-CoV-2 infection might trigger complement accumulation and contribute to renal damage [115].
Furthermore, increased cytokines mediate inflammatory cells adhering to the kidney's endothelial cells, which might affect the kidneys [118].A dysregulated RAS is associated with developing a cytokine storm [109].The reninangiotensin system's major enzyme, ACE2, transforms angiotensin I (Ang I) to Ang (1-9) and downregulates angiotensin II (Ang II) to Ang (1-7), which SARS-CoV-2 recognizes as a major receptor [119].Ang II significantly impacts RAS via functioning on the AT1R and AT2R [109].Between the two, Ang II activates AT1R, which is crucial for fluid balancing since it controls aldosterone secretion in the adrenal cortex.Furthermore, activating the AT1R can enhance thrombosis, inflammation, and fibrosis [120].NF-κB, prostaglandins, vascular endothelial cell growth factor, TNF-α, IL-1b, IL-6, and IFN-g are just a few examples of the proinflammatory substances produced when Ang II combines with kidney resident cells [121,122].Additionally, it increases the cytokine/chemokine synthesis, which attracts immune cells (such as neutrophils, mononuclear cells, T cells, and B cells) to the damage location and intensifies the inflammatory reaction [123].These components encourage kidney and endothelial malfunction, which results in AKI in COVID-19 patients.The solution will lie in addressing RAS abnormalities.

Similarities to Non-COVID-19 AKI with COVID-19 AKI
AKI in individuals with COVID-19 and AKI in sepsis unrelated to COVID have commonalities and distinctions histopathological studies have emphasized.The degree of similarity between sepsis-associated AKI and COVID-19 AKI is intriguing.A secondary effect of severe COVID-19 is acute respiratory distress syndrome (ARDS).Furthermore, there are additional variables linked to ARDS, such as hypoxemia, which can worsen renal vascular impedance, and raised central venous stress carried on by right-sided cardiac arrest, high intrathoracic pressures, or pulmonary vascular thrombi that can worsen interstitial and tubular hydrostatic pressure inside the encapsulated kidney, impairing renal blood flow and GFR in case of both non COVID-19 AKI and COVID-19 AKI [46,130,131].

Early Diagnosis and Drug Management Strategy of AKI in COVID-19
The kidney is an irreplaceable metabolic organ of our body.Several reasons play a crucial role in causing AKI.For example, heart failure, sepsis, hemorrhage, COVID-19, etc. [132].AKI has become a commonly associated issue with COVID-19 infection [62,63].In severe cases, almost half of the individuals (having AKI associated) require kidney replacement [132,133].Furthermore, AKI mediated by COVID-19 is closely related to a higher death rate and health problems when it is progressed.Consequently, early detection offers a crucial therapeutic window for managing AKI to stop the development of chronic renal failure [64,132].
Several factors are considered potential indicators for the early diagnosis of AKI.Treatment is currently utilizing urine output and creatinine level as an indicator of diagnosing AKI in its early stage [132].Serum creatinine (SCR) is typically used to evaluate renal function.But it is not an efficient marker of early diagnosis of AKI.It previously shows glomerular activities but cannot pinpoint acute kidney damage [134,135].SCR is also unspecific in detecting AKI by COVID-19.In addition, several non-renal markers also cause a rise in the SCR level.One example: certain drugs (cimetidine, trimethoprim) can increase SCR levels in an average person [136].
Early AKI diagnosis has come a long way in recent years.Many potential markers have been proposed to detect AKI very early.One is KIM-1 (Kidney injury molecule-1), a possible early feature of acute renal disease, a characteristic glycoprotein primarily found in the renal tubular epithelium [137].SARS-CoV-2 uses the ACE-2 receptor as its primary media to invade the cell.ACE-2 receptor is expressed mainly in renal tubular epithelial cells [57].Podocyte malfunction, acute proximal tubular disruption, and necrosis can all arise from virus inclusion.As a result, KIM-1 level is upregulated and found in urine samples within 24 hours after AKI induced by COVID-19 [135,137].
GGT (γ-glutamyl transpeptidase) is an enzyme.A tubular brush border enzyme is attached to the cytoplasmic membrane's external layer.Evidence suggests a surge in GGT level when renal kidney epithelial cells are damaged as an early diagnostic biomarker of AKI.A multiplex optical analysis method called MUR1-3 is used to identify several connected biomarkers (with GGT) that can help with the early diagnosis of AKI [132,138].
Another early diagnostic marker, NAG (N-acetyl-ßglucosaminidase), is a lysosomal catalyst in renal proximal tubule cells.Moreover, NAG in the urine indicates tubular lesions, as only highly modest levels of tubular indicators can be discovered in the urine of healthy individuals [135,137].The current study's findings demonstrate that KIM-1 may better identify AKI in COVID-19 patients than NAG.But then, additional research in a larger cohort is necessary for this purpose.SARS-CoV-2 mainly affects our respiratory system but is also responsible for many organ dysfunctions.Recent studies suggest the kidney is one of the target sites for COVID-19 inducing acute kidney injury [139].Light and electron microscopy confirmed that SARS-CoV-2 had directly infected the kidneys [140].Studies have shown that the ACE-2 receptor and 3CLpro receptor (3CL protease) play a fundamental role in the virus's life cycle.These two receptors are crucial because they serve as potential therapeutic targets to stop COVID-19 from progressing [141].
Several reports suggest that herbal remedies can be protective in the care of SARS-CoV-2 infected patients by halting the progression of COVID-19.A promising antiviral drug that might stop the coronavirus invasion through various signaling pathways is quercetin, a naturally occurring flavonoid plentiful [142].3CLpro is a protease enzyme.It plays a significant role in the viral replication cycle.Inhibiting the activity of this enzyme is a method of stopping the COVID-19 invasion of kidney cells.In addition, quercetin affects thermal stability, a defining feature of 3CLpro, and halts the virus [143].The entrance receptor of COVID-19 ACE-2 interacts with viral spike protein and induces assimilation of the virus resulting in cytokine storm and inflammation.COVID-19 invasion of kidney cells can be stopped by using quercetin as an agent that can bind with the active site of ACE-2 [144].Another study suggests it can prevent viral spike protein from interacting with certain areas [141,145].Present studies mark the protective role of quercetin in preventing AKI.However, further studies are needed to implement these theories into reality.

Treatment for COVID-19 AKI
Most information used to guide contemporary treatment methods or strategies for individuals with COVID-19 and acute kidney injury (AKI) comes from resource-rich circumstances, generally found in high-income nations.The implementation of these strategies in contexts with limited resources is frequently unfeasible.The regimen of COVID-19 individuals must involve testing for AKI, preventing AKI from developing or getting worse, and resolving AKI, including treating renal failure [146].Depending on the etiology and intensity, AKI may require different treatments and preventive strategies.However, the ideal way to impede AKI in individuals with COVID-19 is yet unknown [146].Preventative plans will be based on a growing comprehension of the mechanism of the disorder [147,148].Most contemporary AKI prevention strategies for COVID-19 individuals are premised on research on AKI in connection with infection and acute hypoxemic respiratory distress [149,150].A report showed that individuals with AKI died in hospitals at a substantially greater rate than those without AKI.In addition, AKI phase progression was linked to a rise in in-hospital fatality.According to records, individuals with phase III and those needing renal replacement treatment had the most incredible fatality rates [151].
Table 2. Some specific strategies for COVID-19 AKI with their advantages.

Avoidance of nephrotoxic drugs
Reduce the chance of developing glomerulonephritis Reduce the likelihood of developing inflammation in the proximal tubules Prevent the development of renal tissue fabrication [152] Regular assessment of urinary discharge and serum creatinine level Indicate glomerular filtration rate Indicate any hindrance to urine abolishment Aids in spotting early indications of kidney damage. [153]

Lung protective ventilation
Enhance kidney function Prevent hemodynamic shifts Reduce the sequences that cause the kidneys' stress from cytokines [154] Managing hypovolemia Helps in the prevention of AKI Maintains appropriate concentrations of creatinine and urea in the blood Aids in preserving organ efficiency. [155] Renal replacements therapy (RRT) Protect the organs and stop COVID-19 and AKI from spreading.
Results in improving fluid equilibrium management and increasing hemodynamic consistency.
RRT is more flexible and minimizes big changes and fluid changes. [156] If a conservative strategy is unsuccessful, renal replacements and extracorporeal assistance may be necessary [155].Extracorporeal organ support (ECOS) and RRT will maintain the organs and stop the advancement of COVID-19 and AKI if they are started immediately [157].Moreover, individuals with COVID-19 who are seriously sick frequently have a hypercoagulable condition.Hence extracorporeal circuit anticoagulation procedures should be utilized [158].
When respiratory fluxes worsen, extracorporeal membrane oxygenation is recommended [155].Since clinical advancement might be rapid, applying successive extracorporeal treatments for immunomodulation, endotoxin and cytokine elimination, and extra-human organ support (ECOS) for different organs must be considered [107].↓ reactive oxygen species (ROS) levels ↑ bioavailability [159] Device: Renal Guard system ↑ urine flow rate ↓ toxic effect of contrast media [160] Procedure: Fluid therapy During operation ↑ cardiac output and perfusion pressure ↑ renal blood flow and glomerular function [161] Other: SUPPORT AKI Clinical Decision Support ↓ mortality for AKI patients [162] AKI I Diagnostic test: Blood and Urine ↑ serum creatinine to 1.5-1.9times from baseline [163] AKI II Diagnostic test: Blood and Urine ↑ serum creatinine to 2.0-2.9 times from baseline [163] AKI III Diagnostic test: Blood and Urine ↑ serum creatinine to ≥3.0 times from baseline [163] (note: ↓ = Decreased/Reduced, ↑ = Increased)

Renal Replacement Therapy
In 1946 Wilhelm Kolf did successful dialysis of a patient.It paved a revolutionary way to treat AKI and reduction of the death rate due to AKI.Despite a debate, it has become an indisputable method to treat acute kidney injury [156].In the recent worldwide pandemic, COVID-19 has emerged as one of the main culprits for emerging respiratory disease outbreaks.But recent studies have shown that AKI is incorporated with COVID-19 [62].In intensive care units (ICUs), 20-25% of patients suffering from acute kidney damage (AKI) need renal replacement therapy (RRT) [164].Since it can eradicate different cytokines, endotoxins, or other toxic chemicals from the human body, it could become a potential treatment [165].
Kidney Disease Improving Global Outcomes (KDIGO) 2012 guideline 5.6.1.suggests using continuous RRT (CRRT) and intermittent RRT as supplemental therapy in AKI individuals because of some adverse effects of RRT that inhibit recovery from AKI.Therefore, the nephrologist providing RRT to severely sick patient with AKI must select the RRT technique that maximizes survivability without continuing AKI [161,166].
Patients in severe situations frequently encounter substantial losses in both macro-and micronutrients.CRRT maintains the nutritional status of these patients by inhibiting more upset and regaining lean body mass with a positive nitrogen balance [167].
In COVID-19 victims, there is currently no way to evaluate cytokine levels immediately.Still, CKRT can be employed to non-selectively cleanse inflammatory cytokines from the body through dispersion, adsorption, and dispersion.Again, some young patients endure intense stress and elevated catabolism in AKI.CKRT controls this instability by providing hemodynamic stability by maintaining fluid balance [161,167].There is evidence that individuals treated with CKRT showed a noticeable decline in mortality rate compared to those who weren't treated with CKRT (54.5 vs. 74.6%,p = 0.032) [168].However, CKRT has some disadvantages, for example: costly (around INR 25,000 to 30,000 daily for the average adult), sterilized fluid bags and unique filter sets, and patient immobilization [161].On the other hand, some studies also suggest that early RRT commencement may increase survival time and provide essential therapy opportunities.As a result, they are reducing all-cause in-hospital mortality.The underlying mechanisms, though, are not yet completely understood [165].Further studies are needed in this process to know about its advantage and disadvantage.

COVID-19 Studies in Kidney Transplant Recipients
A frequent issue, Acute Kidney Injury (AKI), in kidney transplantation, can occur in the donor before organ harvesting and the receiver soon after transplantation.It is either de novo post-transplant acute worsening of graft function or delayed graft function (DGF) [169].Opportunistic infections after transplantation in kidney transplant recipients are typically brought on by viruses, which increase death rates and morbidity [37,170].After a kidney transplant, the risk of developing a viral infection is increased by various factors such as immune suppression, graft rejection, and tissue damage [37,170].
According to a case study, kidney transplant recipients exhibit symptoms comparable to those seen in the general community during a pandemic [171].Lymphopenia, hypoxia, chest crepitation, and elevated C-reactive Protein are some additional clinical signs that could appear in kidney transplant patients reported in the first 10 confirmed cases of COVID-19 among kidney transplant recipients [172].The symptoms of COVID-19 can present many different forms, and the prognosis might vary greatly among kidney transplant recipients, but unfortunately, mortality is high in general [172].Five patients with non-"severe" infections were included in a Chinese study of COVID-19 recipients who received kidney transplants but did not experience mortality [173].An additional Italian investigation on kidney transplant recipients with COVID-19 reported a 25% overall death rate among hospitalized patients [174].Therefore, indepth research is required to evaluate the mortality risk associated with transplant recipients carrying COVID-19 [172].

Conclusion
Patients with COVID-19 frequently have kidney involvement, ranging from proteinuria and hemorrhage to acute kidney injury (AKI), needing renal replacement treatment (RRT; also known as kidney replacement therapy).In addition, high mortality is linked to COVID-19-associated AKI (COVID-19 AKI), which acts as a risk factor for allcause hospital death in COVID-19 patients.Therefore, the putative underlying processes of SARS-CoV2-induced kidney injury are highlighted in the current review.AKI's pathophysiology can be connected to both COVID-specific and non-specific pathways.Regional inflammation has a role in the organ destruction caused by COVID-19, and current research suggests that steroids and IL-6 receptor antagonists may effectively prevent severe AKI.However, more studies are needed to confirm these results and determine how they affect renal recovery.In various cohorts, including in examinations of tissue samples taken several weeks following disease start, a direct viral infection of kidney cells has been found.However, there are currently no treatment approaches that target the kidney, despite advances in understanding the mechanisms leading to renal disease in COVID-19.In addition, there is currently no established treatment for COVID-19-induced AKI.Therefore, more study is required to understand renal involvement better and develop diagnostic, prognostic, and therapeutic approaches for use in clinical settings.

Table 3 .
Different stages of AKI and their interventions.