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Year : 2022  |  Volume : 12  |  Issue : 3  |  Page : 99-104

The Risk of COVID-19 in Patients of Chronic Kidney Disease with Cognitive Dysfunction Like Alzheimer Disease: A Perspective on Erythropoietin as a Potential Adjuvant Therapy

1 Department of Medical Research, Dr V Balaji Dr V Seshiah Diabetes Care and Research Institute, Aminjikarai, Chennai, Tamil Nadu; Department of Medical Research, SRM Medical College Hospital and Research Centre, SRM Institute of Science and Technology, Chennai, Tamil Nadu, India
2 Department of Medical Research, SRM Medical College Hospital and Research Centre, SRM Institute of Science and Technology, Chennai, Tamil Nadu, India
3 Department of Mathematics, Sathyabama institute of science and technology, Chennai, Tamil Nadu, India

Date of Submission28-May-2022
Date of Decision24-Jun-2022
Date of Acceptance29-Jun-2022
Date of Web Publication3-Oct-2022

Correspondence Address:
PhD Venkataraman Prabhu
Associate Professor, Department of Medical Research, SRM Medical College Hospital and Research Centre, SRM Institute of Science and Technology, Kattankulathur – 603203
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijnpnd.ijnpnd_35_22

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Background: The universal risk to mankind, coronavirus disease 2019 (COVID-19), shares etiological cofactors with a variety of diseases, including anemic chronic kidney disease patients (CKD) with cognitive dysfunction like Alzheimer disease (AD). Understanding the shared links between COVID-19 and CKD, as well as cognitive impairment such as AD, might aid in designing therapeutic ways to combat both. Given the need of developing COVID-19 medicine, the connection and symptoms of CKD with cognitive impairment have been reviewed here, with a focus on memory and learning disturbance. Objective: COVID-19 and CKD with cognitive dysfunction share angiotensin-converting enzyme 2 receptors, and AD indicators include amyloid, tau protein, and glycogen synthase kinase-3β. Anemia in patients with CKD and pulmonary fibrosis is frequently treated with recombinant human erythropoietin (rHuEPO). Through nitric oxide stimulation, neuroprotection, and various organ hypoxias, rHuEPO promotes red blood cells (RBC) growth while also assisting oxygen delivery. Results and Conclusions: In COVID-19, rHuEPO may be advantageous. The common etiological variables and manifestations outlined in this review could aid in the development of therapeutic options for COVID-19 and CKD with cognitive impairment, such as AD, and so help to eliminate the ongoing universal risk.

Keywords: ACE2, amyloid β, APP processing, CKD, cognitive impairment, COVID-19, rHuEPO, tau protein

How to cite this article:
Ganesan V, Nehru M, Shankar G, Prabhu V. The Risk of COVID-19 in Patients of Chronic Kidney Disease with Cognitive Dysfunction Like Alzheimer Disease: A Perspective on Erythropoietin as a Potential Adjuvant Therapy. Int J Nutr Pharmacol Neurol Dis 2022;12:99-104

How to cite this URL:
Ganesan V, Nehru M, Shankar G, Prabhu V. The Risk of COVID-19 in Patients of Chronic Kidney Disease with Cognitive Dysfunction Like Alzheimer Disease: A Perspective on Erythropoietin as a Potential Adjuvant Therapy. Int J Nutr Pharmacol Neurol Dis [serial online] 2022 [cited 2022 Dec 6];12:99-104. Available from:

   Introduction Top

Coronaviruses are part of the Nidovirales order and belong to the Coronaviridae family. Coronaviruses are microscopic, measuring 65 to 125 nm in diameter, and containing a single-stranded RNA nucleic material ranging in size from 26 to 32 kbs. The coronavirus family is divided into four subgroups: alpha (α), beta (β), gamma (γ), and delta (δ) coronaviruses.[1] Only mammals are infected by alpha and betacoronaviruses. Birds are infected by gammacoronaviruses and deltacoronaviruses, but some of them can infect mammals as well.[2] In humans, alpha and betacoronaviruses are the most common cause of respiratory illness. In Wuhan, China’s emerging business center, during the first 50 days of the epidemic, a new coronavirus killed >1800 people and infected over 70,000 more. This virus was identified as a coronavirus belonging to the beta community. Chinese researchers have given the virus the name 2019 novel coronavirus (2019-nCoV). The virus was named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by the International Committee on Taxonomy of Viruses (ICTV), and the disease was named coronavirus disease 2019 (COVID-19).[] COVID-19’s mortality, like that of other coronavirus infections, is linked to respiratory dysfunction produced by the host immune system’s overproduction of pro-inflammatory cytokines. As a result of the cytokine storm, acute lung injury/acute respiratory distress syndrome (ALI/ARDS) develops.[6]

   Pathogenesis of COVID-19 Top

COVID-19 is a respiratory disease that affects upper and lower respiratory tracts in the majority of individuals. The most prevalent mode of infection is human-to-human transmission through close contact, which occurs when an infected person coughs or sneezes and sprays droplets from their nose or mouth which may contain virus. Anyone who is within 6 ft of that person can breathe it into their lungs. Surfaces are also thought to contain the virus for different amounts of time depending on their composition.[7] COVID-19 can be transferred after a 2 to 14-day asymptomatic incubation period.[8] After entering the lungs, COVID-19 infects cells that express cell surface receptors like angiotensin-converting enzyme 2 (ACE2), cluster of differentiation 147 (CD147), or extracellular matrix metalloproteinase inducer, as well as leukocyte activation antigen M6, which is expressed in both kidney tubular cells and lung cells.[8],[9] The innate immune response to viral infection in healthy individuals is highly dependent on interferon (IFN) type I responses and their downstream cascade, which culminates in viral replication regulation and the activation of an efficient adaptive immune response.[10] Coronaviruses can diminish the antiviral action of IFN type I, resulting in uncontrolled viral multiplication, an influx of neutrophils and monocytes/macrophages, and a cytokine storm of pro-inflammatory cytokines. Thus, while oxidative stress and inflammation are necessary for COVID-19 infection defense, they can also be damaging if not handled effectively.[11] Inflammatory responses can be exacerbated by activating particular T helper (Th1/Th17) cells. Severe lymphopenia is a symptom of extreme COVID-19, which has been associated to a higher mortality risk.[12]

   COVID-19 with Anemic Chronic Kidney Disease Top

Chronic kidney disease (CKD) affects about 850 million individuals globally. Severe COVID-19 infection can cause kidney damage and acute tubular necrosis (ATN), resulting in proteinuria, hematuria, and an increase in serum creatinine.[13] Currently, the literature regarding COVID-19 with anemic CKD is inadequate. A search of electronic databases, based on PubMed and Scopus, was carried out with the keywords “COVID-19 with anemic CKD” performed on 2019 to till date (i.e., October 6, 2021) disclosed only limited citation, corresponding to a letter to the editor meta-analysis that found a higher incidence of extreme COVID-19 disease in CKD patients (odds ratio: 3.03, 95% confidence interval: 1.09–8.47, I2 = 0.0%, Cochran Q, P = 0.84) after analyzing four studies of 1389 COVID-19 patients, of which 273 (19.7%) had severe disease (odds ratio: 3.03, 95% confidence interval: 1.09–8.47)[14] and review on COVID-19 in CKD.[15] Proteinuria and hematuria were stated to be 44% and 22% on admission, respectively, in a case series of 710 COVID-19 patients.[16] During a computed tomography scan, some patients had elevated serum creatinine levels and edema of the renal parenchyma. On examination under a light microscope, pathological results from six autopsy specimens showed extreme ATN. Further immunohistochemistry analysis showed the existence of the SARS-CoV-2 nucleocapsid protein in the kidneys, indicating that the virus caused direct tubular damage.[17] It is difficult to estimate the exact incidence of CKD in COVID-19 patients.

   Role of ACE2 in COVID-19 with CKD Top

Patients with CKD are more likely to have hypertension, and the two are closely associated pathophysiologic states, with persistent hypertension leading to declining kidney function and deteriorating renal function leading to worsening blood pressure (BP) control.[18] The prevalence of CKD varies from 60% to 90% depending on the stage of the disease and the cause.[19] Hypertension is thought to be a separate risk factor for COVID-19 development and progression. SARS-CoV-2 can infect organs other than respiratory cells, including the kidneys, ileum, and heart, particularly when viremia is present.[15]

SARS-CoV-1 and SARS-CoV-2 use the ACE2 receptor to spread.[20],[21] ACE2 is found in the alveolar epithelial cells of the lungs, the mucosa of the mouth and nose, and other organs such as renal epithelial cells and bladder cells.[22],[23] ACE2 counteracts the activation of the rennin–angiotensin–aldosterone pathway. SARS-CoV-2 can bind to renal epithelial cells, damage them, and throw off the body’s fluid, acid–base, and electrolyte balance. By inducing damage to kidney epithelial cells, SARS-CoV-2 affects erythropoietin and vitamin D endocrine development as well as BP control. Viral penetration into renal epithelial cells increases the likelihood that the kidney will become a viral reservoir until it is cleared elsewhere, and that urine will become an infectious factor. It will be vital to see if any other kidney cells, such as podocytes, interstitial cells, or immune cells, are affected. Given the widespread use of ACE inhibitors and ACE receptor blockers for hypertension, heart disease, and renal disease, it will be crucial to determine whether stopping or incorporating these drugs in acute COVID-19 infections is helpful.[24] Many medical societies have suggested that the health advantages of ACE inhibitors or angiotensin receptor blockers outweigh the potential hazards in COVID-19, although this is a substantial issue that has yet to be addressed [Figure 1].
Figure 1 Pathophysiology of SARS-CoV-2 infection in CKD patients.

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The kidneys also produce more ACE2 than the lungs, heart, or pancreas.[25] Renin–angiotensin–aldosterone systems (RAASs; including ACE2) are activated in renal illness.[26] In this context, local kidney ACE2 levels are elevated in various diabetic nephropathy models, demonstrating that tubular cells make up 90% of kidney mass.[27] SARS-CoV-2 tubular cell infection may be facilitated by elevated tubular cell ACE2 as a result of preexisting pathogenic circumstances. However, because data on the ACE2/SARS-CoV-2 interaction in kidney illness are scarce, speculation on SARS-CoV-2 infection regulation by intrarenal RAAS seems premature at this time. Acute kidney injury (AKI), proteinuria, and hematuria have all been reported in COVID-19 positive patients.[28] At admission, 44% of 701 COVID-19 patients in a hospital in Wuhan had proteinuria, 27% had hematuria, and 13%, respectively, had elevated serum urea, creatinine, and approximate glomerular filtration rate 60 mL/minute/1.73 m2. In addition, 5% of patients developed AKI.[28] However, as previously stated, the study design was unable to distinguish between preexisting CKD and COVID-19-associated kidney injury, and evidence suggests that CKD patients are more likely to develop severe disease necessitating hospitalization.

   COVID-19 In Patients with CKD and Cognitive Impairment, Such as Alzheimer Disease Top

As CKD advances, cognitive disorders become more widespread, potentially impacting up to 60% of CKD patients. In addition, executive control, attention, verbal communication, memory, comprehension, decision-making, problem-solving, and reasoning are all cognitive domains that might be affected in CKD patients.[29] Many research studies support the importance of relationship between CKD with cognitive dysfunction like Alzheimer.[] Concurrently, to date, we have no evidence to support the relationship between COVID-19 and CKD with cognitive dysfunction. COVID-19-related cognitive symptoms have been recorded in just a few studies.

In a study of 29 patients, Miskowiak et al.[34] discovered that 3 to 4 months after COVID-19 infection, 59% to 65% of patients suffer from clinically significant cognitive deficits, with large effect sizes for global memory, verbal learning, and executive functioning. Long-term pulmonary dysfunction and respiratory symptoms, as well as D-dimer levels during acute sickness, have been associated to cognitive deficits, revealing a probable link to a reduction in oxygen flow to the brain. COVID-19 has a significant prevalence of cognitive repercussions and accompanying functional deficits, according to the researchers, which is consistent with current evidence.[34] One of the first spectroscopic imaging-based studies of neurological injury in COVID-19 patients was recently published by Rapalino et al.’s[35] team at Harvard-associated Massachusetts General Hospital (MGH) in Boston. Using a specific magnetic resonance imaging technique, they discovered that COVID-19 patients with neurological symptoms have some of the same metabolic abnormalities in the brain as patients who have had oxygen deficiency (hypoxia) due to other causes, but there are also significant differences.[35]

Researchers, on the other hand, also proposed a new mechanism for RAAS disorders that may be involved in Alzheimer disease (AD). These factors work together to cause extracellular amyloid β (Aβ) deposition, which leads to plaque formation, and intracellular aggregation of hyperphosphorylated tau protein, which leads to tangle formation, which are the hallmarks of AD.[36] Clinical studies have also identified ACE2 and ACE as brain RAAS factors, not only in the regulation of BP and also has shown that ACE2 is reduced in AD in association with increasing Aβ and tau pathology [Figure 2].[37],[38]
Figure 2 Molecular mechanism of CKD patients with cognitive dysfunction like AD.

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Glycogen synthase kinase 3β (GSK3β) is found in the mitochondria and is highly activated. Mitochondrial GSK3β activity regulated by mitochondrial complex I activity increased the development of reactive oxygen species, and disrupted mitochondrial morphology.[39] This effect establishes a relationship between GSK3β and oxidative stress. In addition, review reports have demonstrated that GSK3β is directly causing both phosphorylated tau (pTau) and Aβ accumulation in AD.[40] Based on this report, in our clinical study also, we found that GSK3β is directly causing both pTau and Aβ accumulation in CKD patients with cognitive dysfunction like AD (unpublished data). A recent research discovered a strong negative correlation between GSK3β, plasma AD markers, and the Mini-Mental State Examination (MMSE) and the Wechsler Memory Scale-I (WMS-I), while a positive correlation was discovered between abnormal proteins and the Tower of London (TOL). Accordingly, greater TOL scores are associated with CKD with cognitive dysfunction while higher GSK3β plasma AD markers levels are associated with lower MMSE and WMS I scores.[32]

   Therapeutic Role of Erythropoietin Top

Recombinant human erythropoietin (rHuEPO) is a common treatment for anemia in patients with CKD and pulmonary fibrosis. rHuEPO stimulates red blood cells (RBC) development, while also aiding oxygen transport through nitric oxide stimulation, neuroprotection, and multiple organ hypoxia.[] rHuEPO was also shown to have a protective effect in AD models, decreasing oxidative stress and tau phosphorylation induced by Aβ, and enhancing memory function by reducing endothelial dysfunction at the cellular level.[41] This has been shown to have neuroprotective effects by inhibiting the GSK3β enzymes pass time.[42],[43] GSK-3 inhibitors will block SARS viral replication while simultaneously enhancing CD8+ adaptive T-cell and innate natural killer cell responses.[44] Therapy with rHuEPO improved cellular immunity visible as rejuvenation of the CD8+ T-cell compartment.[45] Recent review indicates via inhibition of the nuclear factor-κB and janus kinase/signal transducers and activators of transcription 3 (JAK-STAT3) signaling pathways, rHuEPO promotes the development of endothelial progenitor cells and reduces inflammatory processes. The effects of rHuEPO on various aspects of ALI/ARDS caused by SARS-CoV-2 infection are discussed.[6] These may be advantageous in risk of COVID-19 on anemic CKD patients with cognitive dysfunction like AD.[46],[47] According to a recent report, a COVID-19 patient who was treated with rHuEPO due to extreme anemia experienced mostly unexplainable rapid symptom relief and viral regression after receiving the drug.[48] As a result, increasing hemoglobin levels strengthens the oxygen supply, preventing hypoxia.

   Conclusion and Future Research Directions Top

The SARS-CoV-2 pandemic has seen the emergence of a new set of COVID-19 and anemic CKD patients with cognitive dysfunction, which could have a severe effect on clinical conditions in these high-risk individuals. As knowledge, rHuEPO can help anemic CKD patients with cognitive dysfunction reduce their risk of COVID-19. Ultimately, we may assume that the rHuEPO therapy has a promising future. Further pharmacogenomics studies and clinical trials are required to better understand the mechanisms underlying the effects of rHuEPO in COVID 19 on anemic CKD patients with cognitive dysfunction.

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Conflicts of interest

There are no conflicts of interest.

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